51-52-5KNAHARQHSZJURB-UHFFFAOYSA-NKNAHARQHSZJURB-UHFFFAOYSA-N
6-Propyl-2-thiouracil6-Propyl-2 thiouracil (PTU)
4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo-
2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone
2-Mercapto-4-hydroxy-6-n-propylpyrimidine
2-Mercapto-4-hydroxy-6-propylpyrimidine
2-Mercapto-6-propylpyrimidin-4-ol
2-Thio-4-oxo-6-propyl-1,3-pyrimidine
2-Thio-6-propyl-1,3-pyrimidin-4-one
6-n-Propyl-2-thiouracil
6-n-Propylthiouracil
6-Propyl-2-thio-2,4(1H,3H)pyrimidinedione
6-Propylthiouracil
NSC 6498
NSC 70461
Procasil
Propacil
propiltiouracilo
Propycil
Propyl-Thiorist
Propylthiorit
propylthiouracil
Propylthiouracile
Propyl-Thyracil
Prothiucil
Prothiurone
Prothycil
Prothyran
Protiural
Thiuragyl
Thyreostat II
URACIL, 4-PROPYL-2-THIO-
Uracil, 6-propyl-2-thio-
DTXSID502120960-56-0PMRYVIKBURPHAH-UHFFFAOYSA-NPMRYVIKBURPHAH-UHFFFAOYSA-N
Methimazole2H-Imidazole-2-thione, 1,3-dihydro-1-methyl-
1,3-Dihydro-1-methyl-2H-imidazole-2-thione
1-Methyl-1,3-dihydroimidazole-2-thione
1-Methyl-1H-imidazole-2-thiol
1-Methyl-2-mercapto-1H-imidazole
1-Methyl-2-mercaptoimidazole
1-Methyl-4-imidazoline-2-thione
1-Methylimidazole-2(3H)-thione
1-Methylimidazole-2-thiol
1-Methylimidazole-2-thione
2-Mercapto-1-methyl-1H-imidazole
2-Mercapto-1-methylimidazole
2-Mercapto-N-methylimidazole
4-Imidazoline-2-thione, 1-methyl-
Basolan
Danantizol
Favistan
Frentirox
Imidazole-2-thiol, 1-methyl-
Mercaptazole
Mercazole
Mercazolyl
Metazolo
Methimazol
Methylmercaptoimidazole
Metothyrin
Metothyrine
Metotirin
N-Methyl-2-mercaptoimidazole
N-Methylimidazolethiol
NSC 38608
Strumazol
Tapazole
Thacapzol
Thiamazol
thiamazole
Thycapzol
Thymidazol
Thymidazole
tiamazol
DTXSID40208207439-96-5PWHULOQIROXLJO-UHFFFAOYSA-NPWHULOQIROXLJO-UHFFFAOYSA-N
ManganeseColloidal manganese
Cutaval
Manganese element
Manganese fulleride
Manganese metal alloy
Manganese-55
manganeso
DTXSID20241697440-47-3VYZAMTAEIAYCRO-UHFFFAOYSA-NVYZAMTAEIAYCRO-UHFFFAOYSA-N
ChromiumAlpaste RRA 030
Alpaste RRA 050
Chromium element
Chromium metal
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GoldAGC Micro
Britecote
Burnish Gold
C.I. Pigment Metal 3
Colloidal gold
Finesphere Gold W 011
Furuuchi 8560
Gold black
Gold element
Gold Flake
Gold Leaf
Keradec
Palegold 5550
Perfect Gold
Shell Gold
Technic 504
DTXSID30646977439-97-6QSHDDOUJBYECFT-UHFFFAOYSA-NQSHDDOUJBYECFT-UHFFFAOYSA-N
MercuryLiquid silver
Mercure
MERCURIC METAL TRIPLE DISTILLED
mercurio
Mercury element
Quecksilber
Quicksilver
UN 2024
UN 2809
DTXSID10241727440-61-1JFALSRSLKYAFGM-UHFFFAOYSA-NJFALSRSLKYAFGM-UHFFFAOYSA-N
UraniumUranium, isotope of mass 238
238U Element
UN 2979 (DOT)
Uranium I
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ArsenicAs
Arsenic black
ARSENIC METAL
arsenico
Grey arsenic
UN 1558
DTXSID40238867440-66-6HCHKCACWOHOZIP-UHFFFAOYSA-NHCHKCACWOHOZIP-UHFFFAOYSA-N
ZincZn
Asarco L 15
C.I. Pigment Black 16
Merrillite
NC-Zinc
Rheinzink
Stapa TE Zinc AT
UF (metal)
UN 1436
Zinc dust
Zinc Dust 3
Zinc Dust 500 mesh
Zinc Dust LS 2
Zinc Dust MCS
Zinc Flakes GTT
ZINC METAL
ZINC MOSSY
ZINC STRIP
ZINC, MOSSY
Zincsalt GTT
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AluminumAisin Metal Fiber
Al 050P-H24
ALC Fine
Alcan XI 1391
Almi-Paste SSP 303AR
Aloxal 3010
Alpaste 00-0506
Alpaste 0100M
Alpaste 0100MA
Alpaste 0100M-C
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Alpaste 0230M
Alpaste 0230T
Alpaste 0241M
Alpaste 0300M
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Alpaste 0539X
Alpaste 0620MS
Alpaste 0625TS
Alpaste 0638-70C
Alpaste 0700M
Alpaste 0780M
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Alpaste 100M
Alpaste 100MS
Alpaste 100MSR
Alpaste 1100M
Alpaste 1100MA
Alpaste 1100N
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Alpaste 1109MA
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Alpaste 1200M
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Alpaste 1260MS
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Alpaste 1830YL
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Alpaste 93-0595
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Alpaste 94-2315
Alpaste 95-0570
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Alpaste 96-2104
Alpaste 97-0510
Alpaste 97-0534
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Alpaste G
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Alpaste NS 7670
Alpaste O 100N
Alpaste O 2130
Alpaste O 300M
Alpaste P 0100
Alpaste P 1950
Alpaste S
Alpaste SAP 110
Alpaste SAP 414P
Alpaste SAP 550N
Alpaste SCR 5070
Alpaste TCR 2020
Alpaste TCR 2060
Alpaste TCR 2070
Alpaste TCR 3010
Alpaste TCR 3030
Alpaste TCR 3040
Alpaste TCR 3130
Alpaste TD 200T
Alpaste UF 500
Alpaste WB 0230
Alpaste WD 500
Alpaste WJP-U 75C
Alpaste WX 0630
Alpaste WX 7830
Alpaste WXA 7640
Alpaste WXM 0630
Alpaste WXM 0650
Alpaste WXM 0660
Alpaste WXM 1415
Alpaste WXM 1440
Alpaste WXM 5422
Alpaste WXM 760b
Alpaste WXM 7640
Alpaste WXM 7675
Alpaste WXM-T 60B
Alpaste WXM-U 75
Alpaste WXM-U 75C
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Aluchrome Ultrafin Super
Alumat 1600
Alumet H 30
aluminio
Aluminium
Aluminium Flake
Aluminum 27
Aluminum atom
Aluminum element
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ALUMINUM PASTE
ALUMINUM PIGMENT
ALUMINUM TURNINGS
Alumi-paste 640NS
Alumipaste 91-0562
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Alumipaste AW 620
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Alumipaste GX 180A
Alumipaste GX 201A
Alumipaste HR 7000
Alumipaste HR 850
Alumipaste MG 11
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Astroflake 40
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Astroflake LG 70
Astroflake Silver N 040
Astroshine NJ 1600
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Atomizalumi VA 200
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Ecka AS 081
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Eterna Brite 651-1
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Friend Color F 500WT
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Hydro Paste 8726
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Hydrolan 3560
Hydrolux Reflexal 100
Hydroshine WS 1001
JISA 51010P
Kryal Z
Lansford 243
LE Sheet 800
Leafing Alpaste
LG-H Silver 25
Lunar Al-V 95
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Metallux 2154
Metallux 2192
Metalure
Metalure 55350
Metalure L 55350
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Metax G
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Mirror Glow 1000
Mirror Glow 600
Mirrorsheen
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Noral Ink Grade Aluminium
Obron 10890
Offset FM 4500
Puratronic
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Reynolds 4-301
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SAP 260PW-HS
SAP-FM 4010
SBC 516-20Z
Scotchcal 7755SE
Serumekku
Setanium 50MIS-H8
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Siberline ST 21030E1
Silvar A
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Silvex 793-20C
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Sparkle Silver 3641
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Sparkle Silver 5271AR
Sparkle Silver 5500
Sparkle Silver 5745
Sparkle Silver 7000AR
Sparkle Silver 7005AR
Sparkle Silver 7500
Sparkle Silver 960-25E1
Sparkle Silver E 1745AR
Sparkle Silver L 1526AR
Sparkle Silver Premier 751
Sparkle Silver SS 3130
Sparkle Silver SS 5242AR
Sparkle Silver SS 5588
Sparkle Silver SSP 132AR
Special PCR 507
Splendal 6001BG
Spota Mobil 801
SSP 760-20C
Stapa Aloxal PM 2010
Stapa Aloxal PM 3010
Stapa Aloxal PM 4010
Stapa Hydrolac BG 8n.1
Stapa Hydrolac BGH Chromal X
Stapa Hydrolac PM Chromal VIII
Stapa Hydrolac W 60NL
Stapa Hydrolac WH 16
Stapa Hydrolac WH 66NL
Stapa Hydrolux 2192
Stapa Hydrolux 8154
Stapa IL Hydrolan 2192-55900G
Stapa Metallic R 607
Stapa Metallux 1050
Stapa Metallux 211
Stapa Metallux 212
Stapa Metallux 2196
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Stapa Mobilux 181
Stapa Offset 3000
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Starbrite 2100
Super Fine 18000
Super Fine 22000
Supramex 2022
Toyo Aluminum 02-0005
Toyo Aluminum 93-3040
Transmet K 102HE
Tufflake 3645
Tufflake 5843
UN 1396
US Aluminum 809
Valimet H 2
Valimet H 3
White Silver 7080N
White Silver 7130N
DTXSID304027315663-27-1DQLATGHUWYMOKM-UHFFFAOYSA-LDQLATGHUWYMOKM-UHFFFAOYSA-L
CisplatinCis
Platinum, diamminedichloro-, (SP-4-2)-
Abiplatin
Biocisplatinum
Briplatin
cis-DDP
cis-Diaminedichloroplatinum
cis-Diaminedichloroplatinum(II)
cis-Diaminodichloroplatinum(II)
cis-Diamminedichloroplatinum
cis-Diamminedichloroplatinum(II)
cis-Dichlorodiamineplatinum(II)
cis-Dichlorodiammineplatinum
cis-Dichlorodiammineplatinum(II)
Cismaplat
cis-Platin
cisplatine
cis-Platine
cisplatino
cis-Platinous diaminodichloride
Cisplatinum
cis-Platinum
cis-Platinum diaminodichloride
cis-Platinum II
cis-Platinum(II) diaminodichloride
cis-Platinum(II) diamminedichloride
cis-Platinumdiamine dichloride
cis-Platinumdiammine dichloride
Cisplatyl
Citoplatino
Lederplatin
lipoplatin
Neoplatin
NSC 119875
Platamine
Platiblastin
Platidiam
Platinex
Platinol
Platinol AQ
Platinoxan
Platinum, diamminedichloro-, cis-
Platistin
Platosin
SPI 077B103
cis-Dichlorodiamine platinum
cis-Dichloro diaminoplatinum II
DTXSID402498314797-73-0VLTRZXGMWDSKGL-UHFFFAOYSA-MVLTRZXGMWDSKGL-UHFFFAOYSA-M
PerchloratePerchlorate ion
Perchlorate ion (ClO41-)
Perchlorate ion(1-)
Perchlorate(1-)
Perchloric acid, ion(1-)
DTXSID6024252CHEBI:60311thyroid hormoneUBERON:0002113kidneyCHEBI:29101sodium(1+)CHEBI:16737creatinineUBERON:0009773renal tubuleCHEBI:30660thyroxineGO:0006590thyroid hormone generationQ000633toxicityGO:0003094glomerular filtrationVT:0005524kidney plasma flow traitGO:0070293renal absorptionMP:0005332abnormal amino acid levelD004106DilatationMP:0011899podocyte vacuolizationGO:0048102autophagic cell deathMI:0613functionMP:0005475abnormal circulating thyroxine level2decreased3occurrence1increasedPropylthiouracil2016-11-29T18:42:222016-11-29T18:42:22Methimazole2016-11-29T18:42:192016-11-29T18:42:19Manganese2022-02-04T14:47:232022-02-04T14:47:23Chromium2022-02-03T11:22:012022-02-03T11:22:01Gold2022-02-07T15:25:562022-02-07T15:25:56Mercury2016-11-29T18:42:192016-11-29T18:42:19Uranium2021-08-05T14:28:502021-08-05T14:28:50Arsenic2021-04-27T00:15:212021-04-27T00:15:21Zinc2022-02-04T15:05:002022-02-04T15:05:00Aluminum2022-02-04T14:42:112022-02-04T14:42:11Cisplatin2022-02-03T11:34:572022-02-03T11:34:57Perchlorate2016-11-29T18:42:262016-11-29T18:42:2610116ratWCS_9606humanWCS_8355Xenopus laevisWCS_7955zebrafishWCS_90988fathead minnow9823Sus scrofaWikiUser_15Sprague-Dawley10090mouseWCS_9031chicken9606Homo sapiensThyroid hormone synthesis, DecreasedTH synthesis, DecreasedCellular<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">The thyroid hormones (TH), triiodothyronine (T3) and thyroxine (T4) are thyrosine</span><span style="color:black">-</span><span style="color:black">based hormones. Synthesis of TH</span><span style="color:black">s is regulated by thyroid-stimulating hormone (TSH) binding to its receptor and thyroidal availability of iodine via the sodium iodide symporter (NIS). Other proteins contributing to TH production in the thyroid gland, including thyroperoxidase (TPO), dual oxidase enzymes (DUOX), and the transport protein pendrin are also necessary for iodothyronine production (Zoeller et al., 2007).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">The production of THs in the thyroid gland and resulting serum concentrations are controlled by a negatively regulated feedback mechanism. Decreased T4 and T3 serum concentrations activates the hypothalamus-pituitary-thyroid (HPT) axis which upregulates thyroid-stimulating hormone (TSH) that acts to increase production of additional THs (Zoeller and Tan, 2007). This regulatory system includes: 1) the hypothalamic secretion of the thyrotropin-releasing hormone (TRH); 2) the thyroid-stimulating hormone (TSH) secretion from the anterior pituitary; 3) hormonal transport by the plasma binding proteins; 4) cellular uptake mechanisms at the tissue level; 5) intracellular control of TH concentration</span><span style="color:black">s</span><span style="color:black"> by deiodinating mechanisms; 6) transcriptional function of the nuclear TH receptor; and 7) in the fetus, the transplacental passage of T4 and T3 (Zoeller et al., 2007).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">TRH and the TSH primarily regulate the production of T4, often considered a “pro-hormone,” and to a lesser extent of T3, the transcriptionally active TH. Most of the hormone released from the thyroid gland into circulation is in the form of T4, while peripheral deiodination of T4 is responsible for the majority of circulating T3. Outer ring deiodination of T4 to T3 is catalyzed by the deiodinases 1 and 2 (DIO1 and DIO2), with DIO1 expressed mainly in liver and kidney, and DIO2 expressed in several tissues including the brain (Bianco et al., 2006). Conversion of T4 to T3 takes place mainly in </span><span style="color:black">the </span><span style="color:black">liver and kidney, but also in other target organs such as in the brain, the anterior pituitary, brown adipose tissue, thyroid and skeletal muscle (Gereben et al., 2008; Larsen, 2009). </span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">In <strong>mammals</strong>, most evidence for the ontogeny of TH synthesis comes from measurements of serum hormone concentrations. And, importantly, the impact of xenobiotics on fetal hormones must include the influence of the maternal compartment since a majority of fetal THs are derived from maternal blood early in fetal life, with a transition during mid-late gestation to fetal production of THs that is still supplemented by maternal THs. In humans, THs can be found in the fetus as early as gestational weeks 10-12, and concentations rise continuously until birth. At term, fetal T4 is similar to maternal levels, but T3 remains 2-3 fold lower than maternal levels. In rats, THs can be detected in the fetus as early as the second gestational week, but fetal synthesis does not start until gestational day 17 with birth at gestational day 22-23. Maternal THs continue to supplement fetal production until parturition. (see Howdeshell, 2002; Santisteban and Bernal, 2005 for review). Due to the maternal factor, the life stage specific impact of TPO inhibition after exposure to environmental chemicals is complex (Ramhoj et al., 2022).</span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Decreased TH synthesis in the thyroid gland may result from several possible molecular-initiating events (MIEs) including: 1) Disruption of key catalytic enzymes or cofactors needed for TH synthesis, including TPO, NIS, or dietary iodine insufficiency. Theoretically, decreased synthesis of Tg could also affect TH production (Kessler et al., 2008; Yi et al., 1997). Mutations in genes that encode requisite proteins in the thyroid may also lead to impaired TH synthesis, including mutations in pendrin associated with Pendred Syndrome (Dossena et al., 2011), mutations in TPO and Tg (Huang and Jap 2015), and mutations in NIS (Spitzweg and Morris, 2010). 2) Decreased TH synthesis in cases of clinical hypothyroidism may be due to Hashimoto's thyroiditis or other forms of thyroiditis, or physical destruction of the thyroid gland as in radioablation or surgical treatment of thyroid lymphoma. 3) It is possible that TH synthesis may also be reduced subsequent to disruption of the negative feedback mechanism governing TH homeostasis, e.g. pituitary gland dysfunction may result in a decreased TSH signal with concomitant T3 and T4 decreases. 4) More rarely, hypothalamic dysfunction can result in decreased TH synthesis. </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Increased fetal </span><span style="color:black">TH</span> <span style="color:black">levels are also possible. Maternal Graves disease, which results in fetal thyrotoxicosis (hyperthyroidism and increased serum T4 levels), has been successfully treated by maternal administration of TPO inhibitors (c.f., Sato et al., 2014). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">It should be noted that different species and different life</span> <span style="color:black">stages store different amounts of TH precursor</span><span style="color:black">s</span><span style="color:black"> and iodine within the thyroid gland. Thus, decreased TH synthesis via transient iodine insufficiency or inhibition of TPO may not affect TH release from the thyroid gland until depletion of stored iodinated Tg. Adult humans may store sufficient Tg-DIT residues to serve for several months to a year of TH demand (Greer et al., 2002; Zoeller, 2004). Neonates and infants have a much more limited supply of less than a week.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">While the </span><span style="color:black">TH</span> <span style="color:black">system is highly conserved across vertebrates, there are some taxon-specific considerations.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Zebrafish and fathead minnows are oviparous <strong>fish</strong> species in which maternal </span><span style="color:black">THs </span><span style="color:black">are transferred to the eggs and regulate early embryonic developmental processes during external (versus intra-uterine in mammals) development (Power et al., 2001; Campinho et al., 2014; Ruuskanen and Hsu, 2018) until embryonic </span><span style="color:black">TH </span><span style="color:black">synthesis is initiated. Maternal transfer of </span><span style="color:black">THs </span><span style="color:black">to the eggs has been demonstrated in zebrafish (Walpita et al., 2007; Chang et al., 2012) and fathead minnows (Crane et al., 2004; Nelson et al., 2016).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Decreases in TH synthesis can only occur after initiation of embryonic TH synthesis. The components of the TH system responsible for TH synthesis are highly conserved across vertebrates and therefore interference with the same molecular targets compared to mammals can lead to decreased TH synthesis (TPO, NIS, etc.) in fish. Endogenous transcription profiles of thyroid-related genes in zebrafish and fathead minnow showed that mRNA coding for these genes is also maternally transferred and increasing expression of most transcripts during hatching and embryo-larval transition indicates a fully functional HPT axis in larvae (Vergauwen et al., 2018). Although the HPT axis is highly conserved, there are some differences between fish and mammals (Blanton and Specker, 2007; Deal and Volkoff, 2020). For example, in fish, corticotropin releasing hormone (CRH) often plays a more important role in regulating thyrotropin (TSH) secretion by the pituitary and thus </span><span style="color:black">TH</span> <span style="color:black">synthesis compared to TSH-releasing hormone (TRH). Also, in most fish species thyroid follicles are more diffusely located in the pharyngeal region rather than encapsulated in a gland.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Decreased TH synthesis is often implied by measurement of TPO and NIS inhibition measured clinically and in laboratory models as these enzymes are essential for TH synthesis. Rarely is decreased TH synthesis measured directly, but rather the impact of chemicals on the quantity of T4 produced in the thyroid gland, or the amount of T4 present in serum is used as a marker of decreased T4 release from the thyroid gland (e.g., Romaldini et al., 1988). Methods used to assess TH synthesis include, incorporation of </span><span style="color:black">radiolabeled </span><span style="color:black">tracer compounds, radioimmunoassay, ELISA, and analytical detection. </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Recently, amphibian thyroid explant cultures have been used to demonstrate direct effects of chemicals on TH synthesis, as this model contains all necessary synthesis enzymes including TPO and NIS (Hornung et al., 2010). For this work THs was measured by HPLC/ICP-mass spectometry. Decreased TH synthesis and release, using T4 release as the endpoint, has been shown for thiouracil antihyperthyroidism drugs including MMI, PTU, and the NIS inhibitor perchlorate (Hornung et al., 2010).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Techniques for </span><em><span style="color:black">in vivo</span></em><span style="color:black"> analysis of </span><span style="color:black">TH</span> <span style="color:black">system disruption among other drug-related effects in fish were reviewed by Raldua and Piña (2014). TIQDT (Thyroxine-immunofluorescence quantitative disruption test) is a method that provides an immunofluorescent based estimate of thyroxine in the gland of zebrafish (Raldua and Babin, 2009; Thienpont et al., 2011; Jomaa et al., 2014; Rehberger et al., 2018). Thienpont used this method with ~25 xenobiotics (e.g., amitrole, perchlorate, methimazole, PTU, DDT, PCBs). The method detected changes for all chemicals known to directly impact TH synthesis in the thyroid gland (e.g., NIS and TPO </span><span style="color:black">inhibitors</span><span style="color:black">), but not those that upregulate hepatic catabolism of T4. Rehberger et al. (2018) updated the method to enable simultaneous semi-quantitative visualization of intrafollicular T3 and T4 levels. Most often, whole body </span><span style="color:black">TH</span><span style="color:black"> level measurements in fish early life stages are used as indirect evidence of decreased </span><span style="color:black">TH</span> <span style="color:black">synthesis (Nelson et al., 2016; Stinckens et al., 2016; Stinckens et al., 2020). Analytical determination of </span><span style="color:black">TH </span><span style="color:black">levels by LC-MS is becoming increasingly available (Hornung et al., 2015).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">More recently, transgenic zebrafish with fluorescent thyroid follicles are being used to visualize the compensatory proliferation of the thyroid follicles following inhibition of </span><span style="color:black">TH</span> <span style="color:black">synthesis</span><span style="color:black"> among others</span><span style="color:black"> (Opitz et al., 2012).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Taxonomic</span></strong><span style="color:black">: This KE is plausibly applicable across vertebrates. Decreased TH synthesis resulting from TPO or NIS inhibition is conserved across vertebrate taxa, with <em>in vivo</em> evidence from humans, rats, amphibians, some fish speci</span><span style="color:black">es, and birds, and <em>in vitro</em> evidence from rat and porcine microsomes. Indeed, TPO and NIS mutations result in congenital hypothyroidism in humans (Bakker et al., 2000; Spitzweg and Morris, 2010), demonstrating the essentiality of TPO and NIS function toward maintaining euthyroid status. Though decreased serum T4 is used as a surrogate measure to indicate chemical-mediated decreases in TH synthesis, clinical and veterinary management of hyperthyroidism and Graves’ disease using propylthiouracil and methimazole, known to decrease TH synthesis, indicates strong evidence for chemical inhibition of TPO (Zoeller and Crofton, 2005).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Life stage</span></strong><span style="color:black">: Applicability to certain life stages may depend on the species and their dependence on maternally transferred </span><span style="color:black">THs</span> <span style="color:black">during the earliest phases of development. The earliest life stages of teleost fish (e.g., fathead minnow, zebrafish) rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). In externally developing fish species, decreases in TH synthesis can only occur after initiation of embryonic TH synthesis. In zebrafish, Opitz et al. (2011) showed the formation of a first thyroid follicle at 55 hours post fertilization (hpf), Chang et al. (2012) showed a first significant TH increase at 120 hpf and Walter et al. (2019) showed clear TH production already at 72 hpf but did not analyse time points between 24 and 72 hpf. TPO inhibition in a homozygous knockout line abolished the T4 production in thyroid follicles of mutant zebrafish with phenotypic abnormalities occurring from 20 dpf onwards but not before 10 dpf (Fang et al., 2022). Therefore, it is still uncertain when exactly embryonic TH synthesis is activated and thus when exactly this process becomes sensitive to disruption. In fathead minnows, a significant increase of whole body TH</span> <span style="color:black">levels was already observed between 1 and 2 dpf, which corresponds to the appearance of the thyroid anlage at 35 hpf prior to the first observation of thyroid follicles at 58 hpf (Wabuke-Bunoti and Firling, 1983). It currently remains unclear when exactly embryonic </span><span style="color:black">TH </span><span style="color:black">production is initiated in zebrafish.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Sex</span></strong><span style="color:black">: The KE is plausibly applicable to both sexes. </span><span style="color:black">THs </span><span style="color:black">are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of </span><span style="color:black">TH</span><span style="color:black"> levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (HernandezāMariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in </span><span style="color:black">TH</span> <span style="color:black">levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.</span></span></span></span></p>
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<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Zoeller RT. Interspecies differences in susceptibility to perturbation of thyroid hormone homeostasis requires a definition of "sensitivity" that is informative for risk analysis. Regul Toxicol Pharmacol. 2004 Dec;40(3):380.</span></span></span></span></p>
<p style="text-align:start"> </p>
2016-11-29T18:41:232022-11-04T09:25:39Occurrence, Kidney toxicityOccurrence, Kidney toxicityOrgan<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">The kidneys are a crucial site of regulation of divalent cation levels in the plasma through filtration, reabsorption, and concentration (cite). On top of their excretion capabilities, the kidneys are also responsible for the production of hormones crucial for hematologic, cardiovascular, and skeletal muscle homeostasis (Bonventre et al., 2010). Nephrons are the functional units of the kidney and each kidney is made up of approximately 1 million nephrons (Bonventre et al., 2010). The nephrons are vital in reabsorption of these cations where 70% of transport has been shown to occur in the proximal tubule (Barbier et al., 2005). The kidneys are thought to be very susceptible to toxicity due to the increased concentration through their filtering structures with the tubular uptake mechanisms, specifically those of the proximal tubule, magnifying intracellular concentrations (Bonventre et al., 2010; Weber et al., 2017). Commonly, biomarkers like serum creatinine (sCr) and blood urea nitrogen (BUN) are utilized to identify kidney toxicity; however, these markers have been identified as nonspecific to the area of the kidney and slow in identification. Bonventre et al. (2010) has explored other biomarkers that may be used to identify segment specific injury. Proximal tubule injury can be identified using: albumin, RPB, NAG, clusterin, osteopontin, a1-microglobulin, and many others. Glomerulus damage can be identified through urinary Cystatin C, b2-microglobulin, a1-microglobulin, albumin, and more (Bonventre et al., 2010). These biomarkers do show some overlap between regions and can indicate damage to various areas of the nephron, though it is important to note the development of these specific techniques and therefore, the ability to develop more tailored and earlier identifying testing procedures. </span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Since there are many essential metals for cellular function, there are also many transporters responsible for facilitating ionic entry into the cell and the designated cellular compartment (cite). Some of these transporters are very specific to a given metal and some are more diverse in the metals they handle, therefore, these transporters can facilitate the transport of toxic metals into the cell, often through mimickery exhibited by those metals (Ballatori, 2002). DMT1 (divalent metal transporter 1) is a strong example of such transporters. The introduction of toxic divalent cations (Cd<sup>2+</sup>, Pb<sup>2+</sup>, Pt<sup>2+</sup>, etc.) is highly problematic in the kidneys due to increased toxicity and occupancy of DMT1 limiting the transport of essential trace elements. DMT1 is an essential transport molecule that is highly expressed in the kidneys, and is responsible for transport of essential trace divalent cations, as well as highly toxic ones; this competition increases strain on the kidneys exposed to toxic heavy metals (Barbier et al., 2005; Ballatori, 2002). DMT1 has been shown to transport Fe, Zn, Mn, Co, Cd, Cu, Ni, and Pb via a proton-coupled, membrane potential dependant mechanism (Ballatori, 2002). Some toxic metals can also enter a cell by forming complexes that mimic endogenous molecules in their structure. Arsenate and vanadate, for example, act as phosphate mimics both for transport and metabolism, assaulting cellular function by the same mechanism as their initial entry; cromate, selenite and molybdate mimic sulfate in a similar way (Ballatori, 2002). Many of the identified transporters fooled by this mimicry have been localized to the brush border membrane of the renal proximal tubule and epithelial cells. Some divalent metals such as Cd, Ba, and Sr have been shown to enter cells through voltage gated calcium channels. Another important example focused on by Ballatori (2002) is the action of inorganic mercury and methyl mercury (MeHg) that were shown to have high affinity for reduced sulfhydryl groups. These groups are seen on the amino acid cysteine, and importantly on glutathione (GSH), a vital enzymatic antioxidant. MeHg mimics methionine to enter the cell, after which it binds to GSH, and interferes with ATP production (Ballatori, 2002). Uranium has been shown to enter the blood rapidly and then either form stable complexes with plasma proteins, due to its high affinity for phosphate, carboxyl and hydroxyl groups, or binds to bicarbonate in the blood (Keith et al., 2013). In the kidneys, uranium can be released from bicarbonate to combine with other small proteins in the kidney tubular walls, disrupting cellular function (Keith et al., 2013). Uranium has been seen to enter the glomerulus, where it is filtered, via endocytosis as UO<sup>+2</sup> binding to anionic sites of proximal tubular epithelial brush borders (Shaki et al., 2012). </span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">To further understand the mode of action of heavy metals within the kidneys, many studies have been conducted to determine the specific region primarily damaged. It is also important to note that variation of results may be found in some studies as experimental conditions as well as other factors may influence the mode of action of some metals. Zamora et al. (1998) found that kidney function decrease and cytotoxicity increase were correlated with uranium ingestion. However, no glomerular injury was detected, indicating that chronic uranium ingestion in rats (0.004 <span style="font-size:11.0pt">µ</span>g/kg to 9 <span style="font-size:11.0pt">µ</span>g/kg body weight) damages the proximal tubule and not the glomerulus (Zamora et al., 1998). Homma-Takeda et al. (2013) identifies the kidneys as the major site of depleted uranium toxicity. Studying the kidneys of rats of varying ages, exposed to 0.1-2mg/kg uranyl acetate, they found that the younger kidneys did not flush the uranium out as well. Accumulation of uranium and its damages was seen in the S3 segment of the proximal tubules (Homma-Takeda et al., 2013). Shaki et al. (2012), assessed the mechanism of depleted uranium-induced nephrotoxicity that revealed damage to the mitochondria isolated from uranyl acetate treated rat kidney cells. The damage included oxidative stress, mitochondrial swelling, mitochondrial membrane potential collapse, cytochrome C release, impaired ATP production, and damage to the electron transport chain complexes. Utilizing rat renal brush border vesicles, Goldman et al. (2006) found that exposure to uranyl acetate induced decreased rates of glucose transport, in part due to a decreased number of sodium-coupled glucose transporters; this decreased the ability of the kidneys to reabsorb glucose properly. Berradi et al. (2008) assessed the red blood cell (RBC) count of rats drinking water containing 40mg DU/L and found that chronic exposure to DU causes RBC reduction, pointing to nephrotoxicity as the kidneys play a major role in RBC synthesis. Heavy metals consistently aggregate in the kidneys, and more specifically in the S3 segment of the proximal tubules. Evidence also suggests <span style="color:black">that uranium and other heavy metals induce nephrotoxicity after endocytosis into cells by disrupting the electron transport chain, inducing oxidative stress. The oxidative stress leads to mitochondrial dysfunction followed by, apoptosis at low doses of uranium and necrosis at high doses of uranium. Finally, this induces renal injury and tissue damage to the proximal tubules, or nephrotoxicity.</span></span></span></p>
<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
<tbody>
<tr>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Assay Type & Measured Content</span></span></strong></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman""><strong>Description</strong></span></span></p>
</td>
<td><strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Dose Range Studied</span></span></strong></td>
<td>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman""><strong>Assay Characteristics</strong></span></span></p>
<p><span style="font-size:12.0pt"><span style="font-family:"Times New Roman""><strong>(Length/Ease of use/Accuracy)</strong></span></span></p>
</td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Kidney Function Assay</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring total urinary protein, albumin, transferrin, b2-microglobulin, retinolbinding protein, brush border tubular antigens, N-acetyl-b-Dglucosaminidase activity, serum and urinary creatine</span></span></p>
<p><span style="font-family:"Times New Roman",serif; font-size:12pt">(de Burbure et al., 2003)</span></p>
</td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“All analyses of a given parameter were performed under similar experimental conditions in the same laboratories within 6mo of collection. Total urinary protein (Prot-T-U) was determined by the Coomassie blue G250 binding method. Albumin (Alb-U), transferrin (Transf-U), β2-microglobulin (β2m-U), and retinolbinding protein (RBP-U) in urine were quantified by latex immunoassay (Bernard & Lauwerys, 1983). Acceptable limits for precision and accuracy of measurements and external quality controls were the same as those described in the Cadmibel study (Lauwerys et al., 1990). The brush border tubular antigens (BBA-U) were analyzed by a sandwich enzyme-linked immunoassay using monoclonal antibodies (Mutti et al., 1985). The total activity of N-acetyl-β-Dglucosaminidase (NAG-T-U) in urine was determined colorimetrically using a kit (PPR Diagnostics Ltd.) as described elsewhere (Price et al., 1996). Only total NAG (NAG-T) was used for the purpose of this study. Serum and urinary creatinine (Creat-U) were measured by the methods of Heinegard and Tiderström (1973), and Jaffé, respectively (Henry, 1965).” (de Burbure et al., 2003)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“The soil contamination in the area varied from 100 to 1700ppm lead (with values higher than 1000ppm in the immediate vicinity of the factories), 0.7 to 233ppm cadmium, and 101 to 22,257ppm zinc, with the highest concentrations being recorded within 500 m of the 2 factories”</span></span></td>
<td> </td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>NAG Assay</strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring N-acetyl-b-D-Glucosaminidase urinary content</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Lim et al., 2016)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“Urinary NAG activity was measured by using NAG Quantitative Kit (Shionogi, Osaka, Japan). After storing a synthetic substrate solution (1 mL) at 37°C for five minutes, the solution was mixed with the supernatant of the urine samples (50 mL) received after centrifugation. After storing it at 37°C for 15 min, stopping solution (2 mL) was added to and mixed with it. By using a spectrophotometer, its fluorescence intensities were measured with a wavelength of 580 nm (</span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057" style="color:#0563c1; text-decoration:underline">13</a></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057" style="color:#0563c1; text-decoration:underline">14</a>). Urinary β2-MG was measured by using Enzygnost β2-MG Micro Kit (Behring Institute, Mannheim, Germany). Its method used the principle of solid phase enzyme-linked immunosorbent assay (ELISA). Monoclonal anti-β2-MG antibody and anti-2-MG-horseradish peroxidase conjugate solution were used. After that, color intensities were measured with a wavelength of 450 nm by using a spectrophotometer (</span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif"><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b13-tr-32-057" style="color:#0563c1; text-decoration:underline">13</a></span></span><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780232/#b14-tr-32-057" style="color:#0563c1; text-decoration:underline">14</a>).” (Lim et al., 2016)</span></span></td>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Pb: 0.0221ppm</strong><br />
(converted from blood Pb <span style="font-size:11.0pt">µg/dL)</span></span></span></p>
<strong><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Cd: 1.08ppm</span></span></strong><br />
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(converted from Urinary Cd μg/g creatinine)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Fast, easy, accurate</span></span></td>
</tr>
<tr>
<td>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><strong>Kidney Dysfunction Assay </strong></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Measuring BUN and creatinine serum blood levels</span></span></p>
<span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">(Shaki et al., 2012)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">“For studies in vivo rats were fasted overnight, then animals were divided into two groups, with six rats in each group. The control group (vehicle) received a single intraperitoneal (i.p.) injection of saline solution (1 ml per 100 g body weight). Uranyl acetate was<br />
dissolved in normal saline. Rats were treated with single intraperitoneal (i.p.) injections of UA in doses 0.5, 1 and 2 mg/kg body weight. These dosages was selected based on previous studies [28], which is sufficient to induce oxidative stress in kidney without causing death and none died within the duration of experiments. Blood urea nitrogen (BUN) and creatinine, marker of kidney dysfunction, were determined by commercial reagents (obtained from Parsazmoon Co., Iran). The rats were killed by decapitation 24 h after injection. The kidney were immediately removed and placed in ice-cold mitochondria isolation medium (0.225 M D-mannitol, 75 mM sucrose, and 0.2 mM EDTA, pH=7.4)” (Shaki et al., 2012)</span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Control, 0.5, 1, 2 mg/kg Uranyl Acetate (UA) </span></span></td>
<td><span style="font-size:12.0pt"><span style="font-family:"Times New Roman",serif">Fast, easy, medium accuracy </span></span></td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Higher order animals (mammals) with functional and complete kidneys </span></span></p>
UBERON:0002113kidneyNot SpecifiedNot Specified<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Al Dera, H. S. (2016). Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats.<em> Saudi Med J, 37</em>(4), 369-378. doi:10.15537/smj.2016.4.13611</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Andjelkovic, M., Djordjevic, A. B., Antonijevic, E., Antonijevic, B., Stanic, M., Kotur-Stevuljevic, J., . . . Bulat, Z. (2019). Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney.<em> International Journal of Environmental Research and Public Health, 16</em>, 247. doi:10.3390/ijerph16020274</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Arzuaga , X., Rieth, S. H., Bathija, A. & Cooper, G. S. (2010) Renal Effects of Exposure to Natural and Depleted Uranium: A Review of the Epidemiologic and Experimental Data, Journal of Toxicology and Environmental Health, Part B, 13:7-8, 527-545, DOI:10.1080/10937404.2010.509015</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Ballatori, N. (2002). Transport of toxic metals by molecular mimicry.<em> Environmental Health Perspectives, 110</em>, 689-694. doi:10.1289/ehp.02110s5689</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Barnes, P., Yeboah, J. K., Gbedema, W., Saahene, R. O., & Amoani, B. (2020). Ameliorative effect of <em>vernonia amygdalina</em> plant extract on heavy metal-induced LIver and kidney dysfunction in rats.<em> Advances in Pharmacological and Pharmaceutical Sciences, 2020</em>, 1-7. doi:10.1155/2020/2976905</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Barbier, O., Jcquillet, G., Tauc, M., Cougnon, M., & Poujeol, P. (2005). Effect of heavy metals on, and handling by, the kidney. Nephron Physiology, 99, 105-110. doi:10.1159/000083981</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="background-color:white"><span style="color:#303030">Bonventre, J. V., Vaidya, V. S., Schmouder, R., Feig, P., & Dieterle, F. (2010). Next-generation biomarkers for detecting kidney toxicity. </span></span><em><span style="background-color:white"><span style="color:#303030">Nature biotechnology</span></span></em><span style="background-color:white"><span style="color:#303030">, <em>28</em>(5), 436–440. </span></span><a href="https://doi.org/10.1038/nbt0510-436" style="color:#0563c1; text-decoration:underline"><span style="background-color:white">https://doi.org/10.1038/nbt0510-436</span></a></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Brzoska, M. M., Kaminski, M., Supernak-Bobko, D., Zwierz, K., & Moniuszko-Jakoniuk, J. (2003). </span><span style="color:black">Changes in the strucutre and function of the kidney of rats chronically exposed to cadmium. I. biochemical and histopathological studies.<em> Arch.Toxicol., 77</em>, 344-352. doi:10.1007/s00204-003-0451-1</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Buelna-Chontal, M., Franco, M., Hernandez-Esquivel, L., Pavon, N., Rodriguez-Zalvala, J. S., Correa, F., . . . Chavez, E. (2017). CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction.<em> Cell Biology International, 41</em>, 1356-1366. doi:10.1002/cbin.10871</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Chtourou, Y., Garoui, E. m., Boudawara, T., & Zeghal, N. (2014). </span><span style="color:black">Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat.<em> </em></span><em><span style="color:black">Environ Toxicol, 29</span></em><span style="color:black">, 1147-1154. doi:10.1002/tox.21845</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Durante, P., Romero, F., Perez, M., Chavez, M., & Parra, G. (2010). </span><span style="color:black">Effect of uric acid on nephrotoxicity induced by mercuric chloride in rats.<em> Toxicology and Industrial Health, 26</em>(3), 163-174. doi:10.1177/0748233710362377</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">García-Niño, W. R., Tapia, E., Zazueta, C., Zatarain-Barrón, Z. L., Hernández-Pando, R., Vega-García, C. C., & Pedraza-Chaverrí, J. (2013). Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening.<em> Evidence-Based Complementary and Alternative Medicine, </em>(424692), 1-19. doi:10.1155/2013/424692</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Goldman, M., Yaari, A., Doshnitzki, Z., Cohen-Luria, R., & Moran, A. (2006). Nephrotoxicity of uranyl acetate: Effect on rat kidney brush border membrane vesicles.<em> Archives of Toxicology, 80</em>(7), 387-393. doi:10.1007/s00204-006-0064-6</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="background-color:white"><span style="color:#212121">Homma-Takeda S, Kokubo T, Terada Y, Suzuki K, Ueno S, Hayao T, Inoue T, Kitahara K, Blyth BJ, Nishimura M, Shimada Y. Uranium dynamics and developmental sensitivity in rat kidney. J Appl Toxicol. 2013 Jul;33(7):685-94. doi: 10.1002/jat.2870. Epub 2013 Apr 26. PMID: 23619997.</span></span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Keith, S., Faroon, O., N., R., Scinicariello, F., Wilbur, S., Ingerman, L., . . . Diamond, G. (2013). <em>Toxicological profile for uranium.</em> </span><span style="color:black">U.S. Department of Health and Human Services. Agency for Toxic Substances and Disease Registry.</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Kharroubi, W., Dhibi, M., Mekni, M., Haouas, Z., Chreif, I., Neffati, F., . . . Sakly, R. (2014). Sodium arsenate induce changes in fatty acids profiles and oxidative damage in kidney of rats.<em> </em></span><em><span style="color:black">Environ Sci Pollut Res, 21</span></em><span style="color:black">, 12040-12049. doi:10.1007/s11356-014-3142-y</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Lunyera, J., & Smith, S. R. (2017). Heavy metal nephropathy: Considerations for exposure analysis. Kidney International, 92, 548-550. doi:http://dx.doi.org/10.1016/j.kint.2017.04.043</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: Heavy metal nephrotoxicity. Revista Nefrologia, doi:10.3265/Nefrologia.pre2012.Jan.10928</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C. (2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.<em> Archives of Toxicology, 81</em>(7), 495-504. doi:10.1007/s00204-006-0173-2</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted uranium on isolated rat kidney mitochondria.<em> Biochimica Et Biophysica Acta - General Subjects, 1820</em>(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Soussi, A., Gargouri, M., & El Feki, A. (2018). Effects of co-exposure to lead and zinc on redox status, kidney variables and histopathology in adult albino rats.<em> Toxicology and Industrial Health, 34</em>(7), 469-480. doi:10.1177/0748233718770293</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Spreckelmeyer, S., Estrada-Ortiz, N., Prins, G. G. H., van der Zee, M., Gammelgaard, B., Sturup, S., . . . Casini, A. (2017). On the toxicity and transportation mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent.<em> Metallomics, 9</em>, 1786. doi:10.1039/c7mt00271h</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Turk, E., Kandemir, F. M., Yildirim, S., Caglayan, C., Kucukler, S., & Kuzu, M. (2019). Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats.<em> Biological Trace Element Research, 189</em>, 95-108. doi:10.1007/s12011-018-1443-6</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">Weber, E. J., Himmelfarb, J., & Kelly, E. J. (2017). Concise review: Current emerging biomarkers of nephrotoxicity.<em> Curr Opin Toxicol., 4</em>, 16-21. doi:10.1016/j.cotox.2017.03.002</span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Yeh, Y., Lee, Y., Hsieh, Y., & Hwang, D. (2011). Dietary taurine reduces zinc-induced toxicity in male wistar rats.<em> Journal of Food Science, 76</em>(4), 90-98. doi:10.1111/j.1750-3841.2011.02110.x</span></span></span></p>
<p style="margin-left:30px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="color:black">Zamora, L. M., Tracy, B. L., Zielinski, J. M., Meyerhof, D. P., & Moss, M. A. (1998). Chronic ingestion of uranium in drinking water: A study of kidney bioeffects in humans.<em> Toxicological Sciences, 43</em>(1), 68-77. doi:10.1006/toxs.1998.242</span></span></span></p>
2016-11-29T18:41:272022-03-04T10:58:19Decreased, Glomerular filtrationDecreased, Glomerular filtrationTissueUBERON:0002113kidneyNot SpecifiedNot Specified2016-11-29T18:41:272017-09-16T10:16:29Decreased, Renal plasma flowDecreased, Renal plasma flowTissueUBERON:0002113kidneyModerateNot Specified2016-11-29T18:41:272017-09-16T10:16:29Decreased, Sodium reabsorptionDecreased, Sodium reabsorptionOrganUBERON:0002113kidneyNot SpecifiedNot Specified2016-11-29T18:41:272017-09-16T10:16:29Increased, Serum creatinineIncreased, Serum creatinineOrganUBERON:0001977serumNot SpecifiedNot Specified2016-11-29T18:41:272017-09-16T10:16:30Occurrence, Cystic dilatation (renal tubule)Occurrence, Cystic dilatation (renal tubule)OrganUBERON:0002113kidneyNot SpecifiedNot Specified2016-11-29T18:41:272017-09-16T10:16:31Occurrence, Cytoplasmic vacuolization (podocyte)Occurrence, Cytoplasmic vacuolization (podocyte)OrganUBERON:0002113kidneyNot SpecifiedNot Specified2016-11-29T18:41:272017-09-16T10:16:31Occurrence, Cytoplasmic vacuolization (Renal tubule)Occurrence, Cytoplasmic vacuolization (Renal tubule)OrganUBERON:0002113kidneyNot SpecifiedNot Specified2016-11-29T18:41:272017-09-16T10:16:31Decreased, Renal ability to dilute urineDecreased, Renal ability to dilute urineOrganNot SpecifiedNot Specified2016-11-29T18:41:272016-12-03T16:37:52 Thyroxine (T4) in serum, DecreasedT4 in serum, DecreasedTissue<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">All iodothyronines are derived from the modification of tyrosine molecules (Taurog, 2000). There are two biologically active thyroid hormones (THs) in serum, triiodothyronine (T3) and T4, and a few less active iodothyronines, reverse T3 (rT3), and 3,3'-Diiodothyronine (3,5-T2). T4 is the predominant TH in circulation, comprising approximately 80% of the TH excreted from the thyroid gland in mammals and is the pool from which the majority of T3 in serum is generated (Zoeller et al., 2007). As such, serum T4 changes usually precede changes in other serum THs. Decreased thyroxine (T4) in serum results from one or more MIEs upstream and is considered a key biomarker of altered TH homeostasis (DeVito et al., 1999).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Serum T4 is used as a biomarker of TH status because the circulatory system serves as the major transport and delivery system for TH delivery to tissues. The majority of THs in the blood are bound to transport proteins (Bartalena and Robbins, 1993). In serum, it is the unbound, or ‘free’ form of the hormone that is thought to be available for transport into tissues. Free hormones are approximately 0.03 and 0.3 percent for T4 and T3, respectively. There are major species differences in the predominant binding proteins and their affinities for THs (see below). However, there is broad agreement that changes in serum concentrations of THs is diagnostic of thyroid disease or chemical-induced disruption of thyroid homeostasis across vertebrates (DeVito et al., 1999; Miller et al., 2009; Zoeller et al., 2007; Carr and Patiño, 2011).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Normal serum T4 reference ranges can be species and lifestage specific. In <strong>rodents</strong>, serum THs are low in the fetal circulation, increasing as the fetal thyroid gland becomes functional on gestational day 17, just a few days prior to birth. After birth serum hormones increase steadily, peaking at two weeks, and falling slightly to adult levels by postnatal day 21 (Walker et al., 1980; Harris et al., 1978; Goldey et al., 1995; Lau et al., 2003). Similarly, in <strong>humans</strong>, adult reference ranges for THs do not reflect the normal ranges for children at different developmental stages, with TH concentrations highest in infants, still increased in childhood, prior to a decline to adult levels coincident with pubertal development (Corcoran et al. 1977; Kapelari et al., 2008).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In some <strong>frog </strong>species, there is an analogous peak in </span><span style="color:black">THs </span><span style="color:black">in tadpoles that starts around embryonic NF stage 56, peaks at </span><span style="color:black">s</span><span style="color:black">tage 62 and the declines to lower levels by </span><span style="color:black">s</span><span style="color:black">tage 56 (Sternberg et al., 2011; Leloup and Buscaglia, 1977). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Additionally, ample evidence is available from studies investigating responses to inhibitors of </span><span style="color:black">TH </span><span style="color:black">synthesis in <strong>fish</strong>. For example, Stinckens et al. (2020) showed reduced whole body T4 concentrations in zebrafish larvae exposed to 50 or 100 mg/L methimazole, a potent TPO inhibitor, from immediately after fertilization until 21 or 32 days of age. Exposure to 37 or 111 mg/L propylthiouracil also reduced T4 levels after exposure up to 14, 21 and 32 days in the same study. Walter et al. (2019) showed that propylthiouracil had no effect on T4 levels in 24h old zebrafish, but decreased T4 levels of 72h old zebrafish. This difference is probably due to the onset of embryonic TH production between the age of 24 and 72 hours (Opitz et al., 2011). Stinckens et al. (2016) showed that exposure to 2-mercaptobenzothiazole (MBT), an environmentally relevant TPO inhibitor, decreased whole body T4 levels in continuously exposed 5 and 32 day old zebrafish larvae. A high concentration of MBT also decreased whole body T4 levels in 6 day old fathead minnows, but recovery was observed at the age of 21 days although the fish were kept in the exposure medium (Nelson et al., 2016). Crane et al. (2006) showed decreased T4 levels in 28 day old fathead minnows continuously exposed to 32 or 100 µg/L methimazole.</span></span></span></span></p>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Serum T3 and T4 can be measured as free (unbound) or total (bound + unbound). Free hormone concentrations are clinically considered more direct indicators of T4 and T3 activities in the body, but in animal studies, total T3 and T4 are typically measured. Historically, the most widely used method in toxicology is the radioimmunoassay (RIA). The method is routinely used in rodent endocrine and toxicity studies. The ELISA method is commonly used as a human clinical test method. Analytical determination of iodothyronines (T3, T4, rT3, T2) and their conjugates, through methods employing HPLC, liquid chromatography, immuno luminescence, and mass spectrometry are less common, but are becoming increasingly available (Hornung et al., 2015; DeVito et al., 1999; Baret and Fert, 1989; Spencer, 2013; Samanidou V.F et al., 2000; Rathmann D. et al., 2015 ). In fish early life stages most evidence for the ontogeny of thyroid hormone synthesis comes from measurements of whole body thyroid hormone levels using LC-MS techniques (Hornung et al., 2015) which are increasingly used to accurately quantify whole body thyroid hormone levels as a proxy for serum thyroid hormone levels (Nelson et al., 2016; Stinckens et al., 2016; Stinckens et al., 2020). It is important to note that thyroid hormones concentrations can be influenced by a number of intrinsic and extrinsic factors (e.g., circadian rhythms, stress, food intake, housing, noise) (see for example, Döhler et al., 1979).</span></span></span></span></p>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Any of these measurements should be evaluated for the relationship to the actual endpoint of interest, repeatability, reproducibility, and lower limits of quantification using a fit-for-purpose approach. This is of particular significance when assessing the very low levels of TH present in fetal serum. Detection limits of the assay must be compatible with the levels in the biological sample. All three of the methods summarized above would be fit-for-purpose, depending on the number of samples to be evaluated and the associated costs of each method. Both RIA and ELISA measure THs by an indirect methodology, whereas analytical determination is the most direct measurement available. All these methods, particularly RIA, are repeatable and reproducible.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Taxonomic</span></strong><span style="color:black">: This KE is plausibly applicable across vertebrates and the overall evidence supporting taxonomic applicability is strong. THs are evolutionarily conserved molecules present in all vertebrate species (Hulbert, 2000; Yen, 2001). Moreover, their crucial role in zebrafish development, embryo-to-larval transition and larval-to-juvenile transition (Thienpont et al., 2011; Liu and Chan, 2002), and amphibian and lamprey metamorphoses is well established (Manzon and Youson, 1997; Yaoita and Brown, 1990; Furlow and Neff, 2006). </span><span style="color:black">T</span><span style="color:black">heir role as environmental messenger via exogenous routes in echinoderms confirms the hypothesis that these molecules are widely distributed among the living organisms (Heyland and Hodin, 2004). However, the role of TH</span><span style="color:black">s</span><span style="color:black"> in the different species depends on the expression and function of specific proteins (e.g receptors or enzymes) under TH control and may vary across species and tissues. As such</span><span style="color:black">,</span><span style="color:black"> extrapolation regarding TH action across species and developmental stages should be done with caution.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">With few exceptions, vertebrate species have circulating T4 (and T3) that are bound to transport proteins in blood. Clear species differences exist in serum transport proteins (Dohler et al., 1979; Yamauchi and Isihara, 2009). There are three major transport proteins in mammals; thyroid binding globulin (TBG), transthyretin (TTR), and albumin. In adult humans, the percent bound to these proteins is about 75, 15 and 10 percent, respectively (Schussler 2000). In contrast, in adult rats the majority of THs are bound to TTR. Thyroid</span><span style="color:black">-</span> <span style="color:black">binding proteins are developmentally regulated in rats. TBG is expressed in rats until approximately postnatal day (PND) 60, with peak expression occurring during weaning (Savu et al., 1989). However, low levels of TBG persist into adult ages in rats and can be experimentally induced by hypothyroidism, malnutrition, or caloric restriction (Rouaze-Romet et al., 1992). While these species differences impact TH half-life (Capen, 1997) and possibly regulatory feedback mechanisms, there is little information on quantitative dose-response relationships of binding proteins and serum hormones during development across different species. Serum THs are still regarded as the most robust measurable key event causally linked to downstream adverse outcomes.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Life stage</span></strong><span style="color:black">: The earliest life stages of teleost fish rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). As a result, T4 levels are not expected to decrease in response to exposure to inhibitors of TH synthesis during these earliest stages of development. In zebrafish, Opitz et al. (2011) showed the formation of a first thyroid follicle at 55 hours post fertilization (hpf), Chang et al. (2012) showed a first significant TH increase at 120 hpf and Walter et al. (2019) showed clear TH production already at 72 hpf but did not analyse time points between 24 and 72 hpf. In fathead minnows, a significant increase of whole body </span><span style="color:black">TH </span><span style="color:black">levels was already observed between 1 and 2 dpf, which corresponds to the appearance of the thyroid anlage at 35 hpf prior to the first observation of thyroid follicles at 58 hpf (Wabuke-Bunoti and Firling, 1983). It is still uncertain when exactly embryonic TH synthesis is activated and how this determines sensitivity to TH </span><span style="color:black">system </span><span style="color:black">disruptors.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Sex</span></strong><span style="color:black">: The KE is plausibly applicable to both sexes. </span><span style="color:black">THs</span> <span style="color:black">are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of </span><span style="color:black">TH</span> <span style="color:black">levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (HernandezāMariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in </span><span style="color:black">TH</span> <span style="color:black">levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.</span></span></span></span></p>
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<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Yen PM. (2001). Physiological and molecular basis of thyroid hormone action. Physiol Rev. 81:1097-1142.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Zoeller RT, Tan SW, Tyl RW. General background on the hypothalamic-pituitary-thyroid (HPT) axis. Crit Rev Toxicol. 2007 Jan-Feb;37(1-2):11-53</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Zoeller, R. T., R. Bansal, et al. (2005). "Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain." Endocrinology 146(2): 607-612.</span></span></span></span></p>
2016-11-29T18:41:232022-10-10T08:52:30f840e911-9b43-4d86-83d8-edb3e3595d6dfc5432cf-a3ad-4e73-ab7f-b4b7aa975f87<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3) are synthesized by NIS and TPO in the thyroid gland as iodinated thyroglobulin (Tg) and stored in the colloid of thyroid follicles across vertebrates. Secretion from the follicle into serum is a multi-step process. The first involves thyroid stimulating hormone (TSH) stimulation of the separation of the peptide linkage between Tg and TH. The next steps involve endocytosis of colloid, fusion of the endosome with the basolateral membrane of the thyrocyte, and finally release of TH into blood. More detailed descriptions of this process can be found in reviews by Braverman and Utiger (2012) and Zoeller et al. (2007).</span></span></span></span></p>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">The weight of evidence linking these two KEs of decreased TH synthesis and decreased T4 in serum is strong. It is commonly accepted dogma that decreased synthesis in the thyroid gland will result in decreased circulating TH (serum T4).</span></span></span></span></p>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">The biological relationship between two KEs in this KER is well understood and documented fact within the scientific community.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">It is widely accepted that TPO inhibition leads to declines in serum T4 levels in adult <strong>mammals</strong>. This is due to the fact that the sole source for circulating T4 derives from hormone synthesis in the thyroid gland. Indeed, it has been known for decades that insufficient dietary iodine will lead to decreased serum TH concentrations due to inadequate synthesis. Strong qualitative and quantitative relationships exist between reduced TH synthesis and reduced serum T4 (Ekerot et al., 2013; Degon et al., 2008; Cooper et al., 1982; 1983; Leonard et al., 2016; Zoeller and Tan, 2007). There is more limited evidence supporting the relationship between decreased TH synthesis and lowered circulating hormone levels during development. Lu and Anderson (1994) followed the time course of TH synthesis, measured as thyroxine secretion rate, in non-treated pregnant rats and correlated it with serum T4 levels. Modeling of TH in the rat fetus demonstrates the quantitative relationship between TH synthesis and serum T4 concentrations (Hassan et al., 2017, 2020; Handa et al., 2021). Furthermore, a wide variety of drugs and chemicals that inhibit TPO are known to result in decreased release of TH from the thyroid gland, as well as decreased circulating TH concentrations. This is evidenced by a very large number of studies that employed a wide variety of techniques, including thyroid gland explant cultures, tracing organification of 131-I and </span><em><span style="color:black">in vivo</span></em><span style="color:black"> treatment of a variety of animal species with known TPO inhibitors (King and May,1984; Atterwill et al., 1990; Brown et al., 1986; Brucker-Davis, 1998; Haselman et al., 2020; Hornung et al., 2010; Hurley et al., 1998; Kohrle, 2008; Tietge et al., 2010).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Additionally, evidence is available from studies investigating responses to TPO inhibitors in <strong>fish</strong>. For example, Stinckens et al. (2020) showed reduced whole body T4 concentrations in zebrafish larvae exposed to 50 or 100 mg/L methimazole, a potent TPO inhibitor, from immediately after fertilization until 21 or 32 days of age. Exposure to 37 or 111 mg/L propylthiouracil also reduced T4 levels after exposure up to 14, 21 and 32 days in the same study. Walter et al. (2019) showed that propylthiouracil had no effect on T4 levels in 24h old zebrafish, but decreased T4 levels of 72h old zebrafish. This difference is probably due to the onset of embryonic TH production between the age of 24 and 72 hours (Opitz et al., 2011). Stinckens et al. (2016) showed that exposure to 2-mercaptobenzothiazole (MBT), an environmentally relevant TPO inhibitor, decreased whole body T4 levels in continuously exposed 5 and 32 day old zebrafish larvae. Several other studies have also shown that chemically induced Inhibition of TPO results in reduced TH synthesis in zebrafish (Van der Ven et al., 2006; Raldua and Babin, 2009; Liu et al., 2011; Thienpont et al., 2011; Rehberger et al., 2018). A high concentration of MBT also decreased whole body T4 levels in 6 day old fathead minnows, but recovery was observed at the age of 21 days although the fish were kept in the exposure medium (Nelson et al., 2016). Crane et al. (2006) showed decreased T4 levels in 28 day old fathead minnows continuously exposed to 32 or 100 µg/L methimazole.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><em><span style="color:black">Temporal Evidence:</span></em><span style="color:black"> In <strong>mammals</strong>, the temporal nature of this KER is applicable to all life stages, including development (Seed et al., 2005). There are currently no studies that measured both TPO synthesis and TH production during development. However, the impact of decreased TH synthesis on serum hormones is similar across all ages in mammals. Good evidence for the temporal relationship comes from thyroid system modeling of the impacts of iodine deficiency and NIS inhibition (e.g., Degon et al., 2008; Fisher et al., 2013). In addition, recovery experiments have demonstrated that serum thyroid hormones recovered in athyroid mice following grafting of in-vitro derived follicles (Antonica et al., 2012).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In <strong><em>Xenopus</em></strong>, it has been shown that depression of TH synthesis in the thyroid gland precedes depression of circulating TH within 7 days of exposure during pro-metamorphosis (Haselman et al., 2020). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In oviparous <strong>fish</strong> such as zebrafish and fathead minnow, the nature of this KER depends on the life stage since the earliest stages of embryonic development rely on maternal </span><span style="color:black">TH</span><span style="color:black">s transferred to the eggs. Embryonic </span><span style="color:black">TH</span> <span style="color:black">synthesis is activated later during embryo-larval development. (See Domain of applicability)</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><em><span style="color:black">Dose-response Evidence</span></em><span style="color:black">: Dose-response data is lacking from studies that include concurrent measures of both TH synthesis and serum TH concentrations. However, data is available demonstrating correlations between thyroidal TH and serum TH concentrations during gestation and lactation during development (Gilbert et al., 2013). This data was used to develop a rat quantitative biologically-based dose-response model for iodine deficiency (Fisher et al., 2013). In <em>Xenopus</em>, dose-responses were demonstrated in both thyroidal T4 and circulating T4 following exposure to three TPO inhibitors (Haselman et al., 2020).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">There are no inconsistencies in this KER, but there are some uncertainties. The first uncertainty stems from the paucity of data for quantitative modeling of the relationship between the degree of synthesis decrease and resulting changes in circulating T4 concentrations. In addition, most of the data supporting this KER comes from inhibition of TPO, and there are a number of other processes (e.g., endocytosis, lysosomal fusion, basolateral fusion and release) that are not as well studied.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">For example, Kim et al. (2015) investigated the adverse effects of Triphenyl phosphate (TPP), a substance that disrupts the thyroid system. Therefore,<strong> Rat pituitary</strong> (GH3) and <strong>thyroid follicular cell lines</strong> (FRTL-5) were studied. In the GH3 cells, TPP led to an upregulation of the expression of important thyroid genes (tsh</span><span style="color:black">, tr </span><span style="color:black">alpha</span> <span style="color:black">and tr </span><span style="color:black">beta</span><span style="color:black">) while T3, a positive control, downregulated the expression of these genes. In FRTL-5 cells, the expression of nis and tpo genes was significantly upregulated, suggesting that TPP stimulates </span><span style="color:black">TH</span> <span style="color:black">synthesis in the thyroid gland.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In <strong>zebrafish larvae </strong>at the age of 7 days post-fertilisation (dpf), TPP exposure resulted in a significant <strong>increase in T3 and T4</strong> concentrations and the expression of genes involved in thyroid hormone synthesis. Exposure to TPP also significantly regulated the expression of genes involved in the metabolism (dio1), transport (ttr) and excretion (ugt1ab) of </span><span style="color:black">TH</span><span style="color:black">s. The down-regulation of the crh and tsh genes in the zebrafish larvae suggests the activation of a central regulatory feedback mechanism that is triggered by the increased T3 levels in vivo. Taken together, these observations indicate that TPP increases </span><span style="color:black">TH</span> <span style="color:black">concentrations in early life stages of zebrafish by disrupting central regulatory and hormone synthesis pathways.</span></span></span></span></p>
<p> </p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In rats, Hassan et al. (2020) demonstrated</span><em><span style="color:black"> in vitro: ex vivo</span></em><span style="color:black"> correlations of TPO inhibition using PTU and MMI and constructed a quantitative model relating level of TPO inhibition with changes in circulating T4 levels. They determined that 30% inhibition of TPO was sufficient to decrease circulating T4 levels by 20%. This is further supported by studies of Hassan et al. (2017) and Handa et al. (2021)</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In <em>Xenopus</em>, Haselman et al. (2020) collected temporal and dose-response data for both thyroidal and circulating T4 which showed strong qualitative concordance of the response-response relationship. A quantitative relationship exists there in, but is yet to be demonstrated mathematically in this species. </span></span></span></span></p>
HighMaleHighFemaleHighAll life stagesHighHighHighHighLowLow<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Taxonomic</span></strong><span style="color:black">: This KER is plausibly applicable across vertebrates. While a majority of the empirical evidence comes from work with laboratory rodents, there is a large amount of supporting data from humans (with anti-hyperthyroidism drugs including propylthiouracil and methimazole), some amphibian species (e.g., frog), fish species (e.g., zebrafish and fathead minnow), and some avian species (e.g, chicken). The following are samples from a large literature that supports this concept: Cooper et al. </span><span style="color:black">(1982; 1983); Hornung et al. (2010); Van Herck et al. (2013); Paul et al. (2013); Nelson et al. (2016); Alexander et al. (2017); Stinckens et al. </span><span style="color:black">(2020).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Life stage</span></strong><span style="color:black">: Applicability to certain life stages may depend on the species and their dependence on maternally transferred thyroid hormones </span><span style="color:black">(TH) </span><span style="color:black">during the earliest phases of development. The earliest life stages of teleost fish rely on maternally transferred THs to regulate certain developmental processes until embryonic TH synthesis is active (Power et al., 2001). As a result, TPO inhibition is not expected to decrease TH synthesis during these earliest stages of development. In zebrafish, Opitz et al. (2011) showed the formation of a first thyroid follicle at 55 hours post fertilization (hpf), Chang et al. (2012) showed a first significant TH increase at 120 hpf and Walter et al. (2019) showed clear TH production already at 72 hpf but did not analyse time points between 24 and 72 hpf. In fathead minnows, a significant increase of whole body </span><span style="color:black">TH</span> <span style="color:black"> levels was already observed between 1 and 2 dpf, which corresponds to the appearance of the thyroid anlage at 35 hpf prior to the first observation of thyroid follicles at 58 hpf (Wabuke-Bunoti and Firling, 1983). It is still uncertain when exactly embryonic TH synthesis is activated and how this determines sensitivity to TH </span><span style="color:black">system </span><span style="color:black">disruptors.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Sex</span></strong><span style="color:black">: The KE is plausibly applicable to both sexes. Thyroid hormones are essential in both sexes and the components of the HPT-axis are identical in both sexes. There can however be sex-dependent differences in the sensitivity to the disruption of thyroid hormone levels and the magnitude of the response. In humans, females appear more susceptible to hypothyroidism compared to males when exposed to certain halogenated chemicals (HernandezāMariano et al., 2017; Webster et al., 2014). In adult zebrafish, Liu et al. (2019) showed sex-dependent changes in thyroid hormone levels and mRNA expression of regulatory genes including corticotropin releasing hormone (crh), thyroid stimulating hormone (tsh) and deiodinase 2 after exposure to organophosphate flame retardants. The underlying mechanism of any sex-related differences remains unclear.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, Grobman WA, Laurberg P, Lazarus JH, Mandel SJ, Peeters RP, Sullivan S. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar;27(3):315-389.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, Peremans K, Manto M, Kyba M, Costagliola S. Generation of functional thyroid from embryonic stem cells. Nature. 2012 491(7422):66-71.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Atterwill CK, Fowler KF. A comparison of cultured rat FRTL-5 and porcine thyroid cells for predicting the thyroid toxicity of xenobiotics. Toxicol In Vitro. 1990. 4(4-5):369-74.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Braverman, L.E. and Utiger, R.D. (2012). Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text (10 ed.). Philadelphia, PA: Lippincott Williams & Wilkins. pp. 775-786. ISBN 978-1451120639.</span></span></span></span></p>
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2016-11-29T18:41:332022-10-10T08:56:38fc5432cf-a3ad-4e73-ab7f-b4b7aa975f87ad97644e-054d-4b34-8944-ae33b2e83f67Not SpecifiedNot Specified2021-09-09T04:47:012021-09-09T04:47:01fc5432cf-a3ad-4e73-ab7f-b4b7aa975f87e29f6739-6fe6-4eb4-9da4-5f00b7fbc698Not SpecifiedNot Specified2021-09-09T04:48:582021-09-09T04:48:58fc5432cf-a3ad-4e73-ab7f-b4b7aa975f876722c868-3e17-4733-ae1a-4c02fb2ee08cNot SpecifiedNot Specified2021-09-09T04:50:152021-09-09T04:50:15f840e911-9b43-4d86-83d8-edb3e3595d6d597b6815-124a-4f5d-9ae4-44b1643a9b3cNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:00597b6815-124a-4f5d-9ae4-44b1643a9b3cad97644e-054d-4b34-8944-ae33b2e83f67Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01597b6815-124a-4f5d-9ae4-44b1643a9b3ce29f6739-6fe6-4eb4-9da4-5f00b7fbc698Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01597b6815-124a-4f5d-9ae4-44b1643a9b3c6722c868-3e17-4733-ae1a-4c02fb2ee08cNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01ad97644e-054d-4b34-8944-ae33b2e83f67550712d0-e3c8-4d75-bfbb-688b1e0d863cNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01ad97644e-054d-4b34-8944-ae33b2e83f671edcfc57-a97d-48fd-9809-ddd9261b10f3Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01ad97644e-054d-4b34-8944-ae33b2e83f6749b44f6e-0d23-4439-9c3a-c93411facb74Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01ad97644e-054d-4b34-8944-ae33b2e83f673f7c1b09-3c87-418e-9b72-8df67304538aNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01e29f6739-6fe6-4eb4-9da4-5f00b7fbc698550712d0-e3c8-4d75-bfbb-688b1e0d863cNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01e29f6739-6fe6-4eb4-9da4-5f00b7fbc6981edcfc57-a97d-48fd-9809-ddd9261b10f3Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01e29f6739-6fe6-4eb4-9da4-5f00b7fbc69849b44f6e-0d23-4439-9c3a-c93411facb74Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01e29f6739-6fe6-4eb4-9da4-5f00b7fbc6983f7c1b09-3c87-418e-9b72-8df67304538aNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:016722c868-3e17-4733-ae1a-4c02fb2ee08c550712d0-e3c8-4d75-bfbb-688b1e0d863cNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:016722c868-3e17-4733-ae1a-4c02fb2ee08c1edcfc57-a97d-48fd-9809-ddd9261b10f3Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:016722c868-3e17-4733-ae1a-4c02fb2ee08c49b44f6e-0d23-4439-9c3a-c93411facb74Not SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:016722c868-3e17-4733-ae1a-4c02fb2ee08c3f7c1b09-3c87-418e-9b72-8df67304538aNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01550712d0-e3c8-4d75-bfbb-688b1e0d863c0d9a7c10-8722-406f-b0a8-a875d4e5434bNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:011edcfc57-a97d-48fd-9809-ddd9261b10f30d9a7c10-8722-406f-b0a8-a875d4e5434bNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:0149b44f6e-0d23-4439-9c3a-c93411facb740d9a7c10-8722-406f-b0a8-a875d4e5434bNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:013f7c1b09-3c87-418e-9b72-8df67304538a0d9a7c10-8722-406f-b0a8-a875d4e5434bNot SpecifiedNot Specified2016-11-29T18:41:352016-12-03T16:38:01Kidney dysfunction by decreased thyroid hormoneKidney dysfunctionUnder development: Not open for comment. Do not citeUnder DevelopmentIncluded in OECD Work Plan1.40adjacentNot SpecifiedHighadjacentNot SpecifiedLowadjacentNot SpecifiedLowadjacentNot SpecifiedLowadjacentNot SpecifiedHighadjacentNot SpecifiedLowadjacentNot SpecifiedLowadjacentNot SpecifiedLowadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighadjacentNot SpecifiedHighnon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLownon-adjacentNot SpecifiedLowHighMaleHighUnspecificHigh1 to < 3 monthsHighAdultsHighNot Specified2016-11-29T18:41:162023-04-29T16:02:57