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AOP: 459

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

AhR activation in the thyroid leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals

Short name
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AhR activation in the thyroid leading to Adverse Neurodevelopmental Outcomes in Mammals

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Prakash Patel PhD; Mathematical Modeller, Cyprotex Discovery Limited, an Evotec Company, Alderley Park, Cheshire, SK10 4TG, UK

Simon Thomas PhD; Head of Modelling and Simulation, Cyprotex Discovery Limited, an Evotec Company, Alderley Park, Cheshire, SK10 4TG, UK

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Prakash Patel   (email point of contact)

Contributors

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  • Prakash Patel
  • Simon Thomas

Coaches

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Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Handbook Version OECD status OECD project
v2.0
This AOP was last modified on June 06, 2023 10:32

Revision dates for related pages

Page Revision Date/Time
Activation, AhR February 28, 2024 05:12
Induction, CYP1A2/CYP1A5 May 30, 2018 14:24
Increase, Oxidative Stress March 03, 2022 10:40
Thyroid hormone synthesis, Decreased November 04, 2022 09:25
Thyroxine (T4) in serum, Decreased October 10, 2022 08:52
Thyroxine (T4) in neuronal tissue, Decreased April 04, 2019 09:13
Hippocampal gene expression, Altered August 11, 2018 09:26
Hippocampal Physiology, Altered August 11, 2018 09:41
Cognitive Function, Decreased August 09, 2018 11:55
Activation, AhR leads to Induction, CYP1A2/CYP1A5 May 07, 2018 08:09
Induction, CYP1A2/CYP1A5 leads to Increase, Oxidative Stress May 04, 2023 09:33
Increase, Oxidative Stress leads to TH synthesis, Decreased May 23, 2023 11:58
TH synthesis, Decreased leads to T4 in serum, Decreased October 10, 2022 08:56
T4 in serum, Decreased leads to T4 in neuronal tissue, Decreased April 04, 2019 10:50
T4 in neuronal tissue, Decreased leads to Hippocampal gene expression, Altered August 11, 2018 19:18
Hippocampal gene expression, Altered leads to Hippocampal Physiology, Altered April 12, 2023 11:28
Hippocampal Physiology, Altered leads to Cognitive Function, Decreased August 11, 2018 19:24
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) February 09, 2017 14:32
PCB 126 April 20, 2023 20:20
Polychlorinated biphenyl November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Polychlorinated biphenyls (PCBs) and dioxins are environmental contaminatants whose prenatal exposure in humans and exposure in breast milk is correlated to a specific set of mental impairments (Boucher et al. 2009, Boersma and Lanting 2000, Koopman-Esseboom et al. 1996). What the main mechanism(s) of causing these delays for the various PCBs and dioxins is unclear, but studies in rodents regarding 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and "dioxin-like" PCBs like PCB-126 that it could be caused by lowering maternal and subsequently foetal thyroxine (T4) levels in the brain.

This AOP summarises the findings that chemicals that are AhR receptor agonists can reduce T4 levels in the plasma in rodents and possibly humans and lead to brain changes in neonates, via the increasing of reactive oxygen species (ROS) in the thyroid reducing the secretion rate of T4 in the thyroid.  The problem is that AhR agonists TCDD and dioxin-like PCBs (PCB-126, PCB-169) have multiple effects on several organs as AhR receptor is present in these organs, and especially in the liver whose effect on the liver has been relatively well-characterised (summarised in AOP 458: AhR activation in the liver leading to Subsequent Adverse Neurodevelopmental Outcomes in Mammals).

This AOP was created in order to collate and summarise information around the reduction of T4 levels in the plasma by endocrine disruptors interfering with thyroid hormone secretion via the activation of CYPs. A short summary:

  1. Chemical activates AhR
  2. UGT activity in the thyroid increases
  3. CYP activity in the thyroid increases, generating more reactive oxygen species (ROS)
  4. ROS affects pathways that reduce secretion of T4 by the thyroid
  5. Reduction of plasma T4
  6. Adverse outcomes

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

This AOP was developed as part of the ScreenED project, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 825745

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

 

This AOP summarises the effect of AhR activation leading to thyroid dysfunction, whilst also summarising evidence of hippocampal and mental effects on rodents of TCDD and various PCBs, although the effects on the AhR receptor on the liver metabolism of T4 is probably more dominant. Relevant publications were found by searching through PubMed for terms such as "AhR" "thyroxine" "TCDD" "T4", "CYP", "ROS", "reactive oxygen species", "oxidative stress".

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 18 Activation, AhR Activation, AhR
KE 850 Induction, CYP1A2/CYP1A5 Induction, CYP1A2/CYP1A5
KE 1969 Increase, Oxidative Stress Increase, Oxidative Stress
KE 277 Thyroid hormone synthesis, Decreased TH synthesis, Decreased
KE 281 Thyroxine (T4) in serum, Decreased T4 in serum, Decreased
KE 280 Thyroxine (T4) in neuronal tissue, Decreased T4 in neuronal tissue, Decreased
KE 756 Hippocampal gene expression, Altered Hippocampal gene expression, Altered
KE 758 Hippocampal Physiology, Altered Hippocampal Physiology, Altered
AO 402 Cognitive Function, Decreased Cognitive Function, Decreased

Relationships Between Two Key Events (Including MIEs and AOs)

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Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Foetal High
Birth to < 1 month High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
mouse Mus musculus Moderate NCBI
rat Rattus norvegicus Moderate NCBI
human Homo sapiens Low NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed Moderate

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Domain of Applicability

  • Chemicals: This AOP applies to a wide range of chemicals structures that activate AhR either in vivo or in vitro, but one needs to understand that not all AhR agonists do not produce toxic effects
  • Sex: This AOP applies to males and females. Disruption of thyroid hormone regulation during foetal and early postnatal development, but the subsequent adverse impacts on nervous system development may differ and be more severe in males than females (Seo et al. 1999, Rice 1999).
  • Life stages: The relevant life stages for this AOP are fetal and early postnatal ages during critical windows of nervous system development where thyroid hormones guide normal development of the brain. There are clear windows of developmental susceptibility and different brain regions show distinct ontogenetic profiles for TH requirements. Distinct phenotypes have been described in both humans and animal models for different periods of TH insufficiency. The influence of maternal thyroid status prior to onset of fetal thyroid function is an important consideration. This AOP does not apply to adult life states.
  • Taxonomic: Based on the majority of the available evidence the taxonomic applicability domains of this AOP is mammals. Most evidence for this AOP has been gathered primarily from laboratory rodents and humans.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Key Events

Direct evidence

Indirect evidence

No or contradictory evidence

MIE 18

AhR activation

TCDD and various PCBs can be confirmed to be agonists of AhR from both the EROD (Petrulis et al. 1999) and CALUX assay (Murk et al. 1996) to estimate exposure and activation of the AhR-ARNT pathways.

KE 850

Induction, CYP1A2/CYP1A5

TCDD – upregulation of CYP1A1 and CYP1A2 in mouse pups heterozygous for AhR +/- gene but far less upregulation of CYPs for pups homozygous for  the AhR -/- gene whose mothers were administered 10 ug/kg TCDD on gestation day 12.5 (Nishimura et al. 2005)

A marked induction of CYP1A1 mRNA in pups of Holtzmann rat mothers (a TCDD sensitive strain) administered TCDD on gestational day 15 and perinatal exposure to TCDD was found (Nishimura et al. 2003)

TCDD – Generally accepted that TCDD and structural analogues induce CYP1A1 and CYP1A2 in animals and humans (Poland and Knutson 1982, Goldstein and Safe 1989, Silbergeld and Gasiewicz 1989 – refs in Tritscher et al. 1992)

SD rats were administered TCDD and CYP1A1 and CYP1A2 were induced in liver microsomes in a dose dependent manner (Tritscher et al. 1992)

Male F344/NCr rats given a single dose of TCDD or five days of various PCBs increased RNA expression of CYP1A1 and EROD assay activity in liver microsomes (Dragnev et al. 1995)

The Cyp1A1 gene was upregulated in Hepa1c1c7 cells and mouse C57BL/6 mouse liver samples on exposure to TCDD and PCB-126 (Nault et al. 2013)

Porcine thyrocytes exposed to TCDD and PCB-126 have increased expression of CYP1A1 (Pocar et al. 2006)

KE 1969

Increase, Oxidative Stress

ROS production is tightly linked to the catalytic circle of CYP enzymes, more precisely to a phenomenon called “uncoupling”. Briefly, in the presence of NADPH, CYP monooxygenases reduce molecular oxygen to introduce one oxygen equivalent into the substrate and the second one into water.

By analysing the stoichiometry of this reaction, it became evident that most CYP enzymes expend more oxygen than needed to monooxygenate the substrates - in fact the small amounts of H2O2 are frequently formed as a by-product of this catalysis (Vogel et al. 2020)

TCDD-induced CYPs are a major source of ROS in hepatocytes, as measured in the H2DCFDA assay and the presence of increased 8-oxo-dG (Knerr et al. 2006)

Overexpression of CYP1A1 and CYP1A2 in human lymphoblast derived microsomesstimulated production of ROS such as superoxide radicals (Puntanulo and Cedarbaum 1998)

TCDD - intraperitoneal treatment of 5ug/kg TCDD in female C57BL/6J mice for three consecutive days produced increased hepatic glutathione levels 2-fold within one week and last for 8 weeks, with urinary levels of hydroxydeoxyguanosine - a product of DNA base oxidation and repair - remain elevated 20-fold for 8 weeks after treatment. (Shertzer et al. 1998)

TCDD - when applied to the hepatoma cell line Hepa1c1c7 results in an elevation in the excretion rate of 8-oxoguanine, a biomarker of oxidative DNA damage. (Park et al. 1996)

TCDD did not increase ROS in HepG2 cells in the H2DCFDA assay or increase 8-oxo-dG (Knerr et al. 2006)

KE 277

Thyroid hormone synthesis, Decreased

In chicken ex vivo thyroids, there was a reduction of T3 and T4 secretion after 24h exposure to TCDD or PCB 126. TCDD and PCB 126 significantly increased mRNA expression of TPO and TG genes, but only PCB 126 reduced NIS genes (Katarzyńska et al. 2015)

Chicken thyroid explants were incubated in medium supplemented with TSH (250 mU/ml), PCB118, PCB153, 4-OH-PCB107, and 3-OH-PCB153 (0.5 × 10-8 M), and TSH together with each PCB and OH-PCB. Except for 4-OH-PCB107, all applied PCBs and OH-PCBs inhibited basal and TSH-stimulated T4 secretion. Moreover, they increased basal and reduced TSH-stimulated T3 secretion. (Kowalik and Sechman 2022)

Porcine thyrocytes exposed to TCDD and PCB-126 induced a significant downregulation in the expression of NIS and cathepsin B, enzymes involved in the uptake of iodine and release of T4 from thyroglobulin hence T4 secretion (Pocar et al. 2006)

Hydrogen peroxide is necessary for thyroperoxidase to work, and is most probably generated by DUOX1 and DUOX2. Patients with mutations on DUOX2 gene experience congenital hypothyroidism (Moreno et al. 2002)

KE 281

Thyroxine (T4) in serum, Decreased

There are no other primary sources of T4 in the body so a lack of secretion of T4 by the thyroid would lead to a lack of T4 in the serum.

Both PCB-126 and TCDD reduce serum T4 levels in chronic studies in rats (Kohn et al. 1996, NTP 2006), although the dominant effect is likely to be increase in T4 metabolism in the liver rather than secretion by the thyroid (AOP 458)

KE 280

Thyroxine (T4) in neuronal tissue, Decreased

Several studies have demonstrated that foetal brain TH levels, previously decreased by maternal exposure to TH synthesis inhibitors or thyroidectomy, recovered following maternal supply of T4 (e.g. Calvo et al. 1990). However, there are no studies with direct infusion of T4 or T3 directly into brain.

The upregulation of deiodinase has been shown to compensate for some loss of neuronal T3 (Escobar-Morreale et al. 1995; Escobar-Morreale et al. 1997).

Indirect evidence shows that T4 replacement that brings circulating T4 concentration back to physiological levels normal, leads to recovery of brain TH and prevents downstream effects including alterations in cell morphology, differentiation and function.

PCB-118: lower-TEQ congener (PCB-118) acted via the TH pathway in the rat foetus while the higher-TEQ congener (PCB-126) did not and acted mainly via reducing maternal thyroid hormone levels (Fritsche et al. 2005, Gauger et al. 2004.)

KE 756

Hippocampal gene expression, Altered

Hippocampal Gene Expression, Altered: It is well established specific genomic pathways underlie the progression of a number of neurodevelopmental processes in the hippocampus. There is some evidence from ex vivo studies that administration of growth factors will reverse the hippocampal dysplasia seen in Jacob/Nsfm knockout mice (Spilker et al., 2016). Less is known about the impact of hormone replacement on TH-responsive gene expression and the qualitative and quantitative relationships between altered TH-dependent gene expression in this brain region and altered hippocampal cytoarchitectural anatomy.

KE 758

Hippocampal Physiology, Altered

Hippocampal anatomy, altered: It is well accepted that normal hippocampal anatomy is critical for hippocampal physiological function, and that alterations in anatomy lead to altered neuronal activity in the hippocampus (Lee et al., 2015; Grant et al., 1992; Spilker et al., 2016). Hippocampal physiology, altered: It is a well-accepted assertion that hippocampal synaptic integrity and neuronal plasticity are essential for spatial information processing in animals and spatial and episodic memory in humans. However, other brain regions also can influence these complex behaviors. Limited data from studies in BDNF knockout animals demonstrate that deficits in hippocampal synaptic transmission and plasticity, and downstream behaviors can be rescued with recombinant BDNF (Aarse et al., 2016; Andero et al., 2014).

The relative size of the IIP-MF in females and males. The IIP-MF was smaller in TCDD exposed female AhR-/- mice with respect to their genotype control group. (Powers et al. 2005)

Pregnant Sprague-Dawley rats were given a consecutive daily dose of TCDD (200 or 800 ng/day/kg) or an equivalent volume of vehicle by gavage on gestational days 8-14 as the prenatal TCDD exposure model. When the male pups grew to adults, morphology and number of neurons in the hippocampus CA1 region was not affected, although the activity of astrocytes in the same region was significantly reduced (Zhang et al. 2018)

AO 402

Cognitive Function, Decreased

TCDD exposed female AhR-/- mice performed worse on the spatial water maze task than non exposed mice (Powers et al. 2005)

Pregnant Sprague-Dawley rats were given a consecutive daily dose of TCDD (200 or 800 ng/day/kg) or an equivalent volume of vehicle by gavage on gestational days 8-14 (GD 8-14). The results of the behavioural tests showed that gestational TCDD exposure induced premature motor activity and earlier eyes-opening, but lead to serious deficits of spatial memory and learning ability in the adult male offspring. (Zhang et al 2018)

Monkeys exposed to TCDD perinatally exhibited retarded learning of the shape reversals (Shantz and Bowman 1994)

Pregnant Long-Evans rats were dosed by gavage with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or at a dose of 0, 200, or 800 ng/kg on gestational day 15, and the offspring was tested during adulthood. Paired-associate learning was found to be impaired in the TCDD-200 and group, but not in either group exposed to 800 ng/kg TCDD (Kakeyama et al. 2014)

Long-Evans dams dosed at h 0, 0.25, or 1.0 ug/kg/day PCB-126 Monday to Friday beginning 5 weeks before and continuing through gestation and lactation.  On the spatial delayed alternation task, there was no convincing evidence for impairment as a result of PCB exposure on adult male pups, as assessed by overall accuracy of performance and measures of perseverative and other types of inappropriate responding (Rice 1999).

Time-mated Sprague–Dawley rats were gavaged with eitherTCDD (0.1 mg/kg/day) or corn oil vehicle on gestation days 10–16. On day 80, both male and female TCDD-exposed grown-up pups showed a deficit in learning on the visual partial discrimination-reversal learning task, but TCDD-exposed male rats displayed a pronounced decrease in errors relative to control males in the Morris Water Maze task. There was no difference in the performance of TCDD exposed rats in the radial arm maze task. (Seo et al. 1999)

Pregnant Sprague–Dawley rats (10 per dose) received either 0 or 0.1 mg/kg TCDD orally in corn oil from GD 10 to GD 16. One male and one female from each litter were tested beginning at 100 days of age. the results of the current study underscore the fact that (1) alterations in cognitive function observed following early TCDD exposure are very subtle and (2) under some conditions, learning is actually facilitated, rather than impaired, in TCDD-exposed animals. (Widholm et al. 2003)

Monkeys exposed to TCDD perinatally showed a slight facilitation of learning on both delayed spatial alternation and spatial reversal learning tasks (Seegal and Schantz 1994)

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Biological plausibility

Biological plausibility refers to the structural or functional relationship between the key events based on our fundamental understanding of "normal biology".

In general, the biological plausibility and coherence linking AhR activation by PCBs and dioxins to decreases in circulating concentrations of THs is great; the biological plausibility of decreases in circulating concentrations of THs, to adverse impacts in the developing hippocampus and subsequent cognitive behaviours is solid (AOP 42), but the evidence via the reduction of thyroid hormone secretion by the thyroid is weak.

Concordance of dose-response relationships:

There are several studies that include correlative evidence between exposure to AhR agonists TCDD (Kohn et al. 1996, NTP 2006) and PCB-126 (NTP, 2006) to downstream KEs up until the reduction of T4 in the plasma (KE 281). Referring to the AOPs 42 and 54, there is ample evidence the reduction of plasma T4 correlates to neurological deficits. Again, the evidence that it’s from activation of AhR leading to the reduction of thyroid hormone secretion by the thyroid is weak.

Consistency

Uncertainties, inconsistencies, and data gaps:

The effect of thyroid hormone secretion by the thyroid is not routinely measured in animals and humans (Tal et al 1999, Karazynska et al 2016) and especially in the case of the effect of thyroid disruptors. One could gauge this in vivo by measuring the balance of T4 in the plasma and other tissues.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Currently, it is poor as T4 secretion of the thyroid in vivo is not routinely measured or calculated in regards to the impact by thyroid disruptors.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Aarse J, Herlitze S, Manahan-Vaughan D. The requirement of BDNF for hippocampal synaptic plasticity is experience-dependent. Hippocampus. 2016;26(6):739-5

Andero R, Choi DC, Ressler KJ. (2014). BDNF-TrkB receptor regulation of distributed adult neural plasticity, memory formation, and psychiatric disorders. Prog Mol Biol Transl Sci.122:169-92

Calvo R, Obregón MJ, Ruiz de Oña C, Escobar del Rey F, Morreale de Escobar G.  Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3'-triiodothyronine in the protection of the fetal brain.  J Clin Invest. 1990;86(3):889-99

Dragnev KH, Nims RW, Fox SD, Lindahl R, Lubet RA. Relative potencies of induction of hepatic drug-metabolizing enzyme genes by individual PCB congeners. Toxicol Appl Pharmacol. 1995;132(2):334-42

Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, Morreale de Escobar G.Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest. 1995;96(6):2828-38.

Escobar-Morreale HF, Obregón MJ, Hernandez A, Escobar del Rey F, Morreale de Escobar G. (1997). Regulation of iodothyronine deiodinase activity as studied in thyroidectomized rats infused with thyroxine or triiodothyronine. Endocrinology. 138(6):2559-68

Fritsche E, Cline JE, Nguyen NH, Scanlan TS, Abel J. Polychlorinated biphenyls disturb differentiation of normal human neural progenitor cells: clue for involvement of thyroid hormone receptors. Environ Health Perspect. 2005;113(7):871-6

Gauger KJ, Kato Y, Haraguchi K, Lehmler HJ, Robertson LW, Bansal R, Zoeller RT. Polychlorinated biphenyls (PCBs) exert thyroid hormone-like effects in the fetal rat brain but do not bind to thyroid hormone receptors. Environ Health Perspect. 2004;112(5):516-23

Goldstein, J. A., and Safe. S. Mechanism of action and structure-activity relationship for the chlorinated dibenzo-p-dioxins and related compounds. In: R. D. Kimbrough and A. A. Jensen (eds.). Halogenated biphenyls, terphenyls, naphthalenes, dibenzodioxins and related products, pp. 239-293. Amsterdam: Elsevier Science Publishers B. V. (Biomedical Division). 1989

Grant SG, O'Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER. Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992;258(5090):1903-10

Kakeyama M, Endo T, Zhang Y, Miyazaki W, Tohyama C. Disruption of paired-associate learning in rat offspring perinatally exposed to dioxins. Arch Toxicol. 2014;88(3):789-98

Katarzyńska D, Hrabia A, Kowalik K, Sechman A. Comparison of the in vitro effects of TCDD, PCB 126 and PCB 153 on thyroid-restricted gene expression and thyroid hormone secretion by the chicken thyroid gland. Environ Toxicol Pharmacol. 2015;39(2):496-503

Knerr S, Schaefer J, Both S, Mally A, Dekant W, Schrenk D. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells. Mol Nutr Food Res. 2006;50(4-5):378-84

Kohn MC, Sewall CH, Lucier GW, Portier CJ. A mechanistic model of effects of dioxin on thyroid hormones in the rat. Toxicol Appl Pharmacol. 1996;136(1):29-48

Kowalik K, Sechman A. In vitro effects of polychlorinated biphenyls and their hydroxylated metabolites on the synthesis and metabolism of iodothyronines in the chicken (Gallus domesticus) thyroid gland. Gen Comp Endocrinol. 2022;318:113989

Lee KH, Lee H, Yang CH, Ko JS, Park CH, Woo RS, Kim JY, Sun W, Kim JH, Ho WK, Lee SH. Bidirectional Signaling of Neuregulin-2 Mediates Formation of GABAergicSynapses and Maturation of Glutamatergic Synapses in Newborn Granule Cells of Postnatal Hippocampus. J Neurosci. 2015;35(50):16479-93

Moreno JC, Bikker H, Kempers MJ, van Trotsenburg AS, Baas F, de Vijlder JJ, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med. 2002;347(2):95–102

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