Increase, Orofacial clefting

51-28-5

UFBJCMHMOXMLKC-UHFFFAOYSA-N

2,4-Dinitrophenol

DNP 1,3-Dinitro-4-hydroxybenzene 1-Hydroxy-2,4-dinitrobenzene 2,4-dinitrofenol Aldifen Dinitrophenol DINITROPHENOL, 2,4- Dinofan Fenoxyl Carbon N NSC 1532 Phenol, α-dinitro- UN 1320 UN 1599 α-Dinitrophenol Phenol, 2,4-dinitro-

DTXSID0020523

87-86-5

IZUPBVBPLAPZRR-UHFFFAOYSA-N

Pentachlorophenol

PCP Phenol, pentachloro- 1-Hydroxy-2,3,4,5,6-pentachlorobenzene 1-Hydroxypentachlorobenzene Chlorophenasic acid CHLOROPHENATE Dowicide EC 7 Dura Treet II Fungifen Grundier Arbezol Lauxtol Liroprem NSC 263497 Penchlorol Pentachlorphenol Perchlorophenol Permasan Phenol, 2,3,4,5,6-pentachloro- Pole topper Pole topper fluid Preventol P Santophen 20 Satophen UN 3155 Witophen P Woodtreat A 2,3,4,5,6-Pentachlorophenol

DTXSID7021106

3380-34-5

XEFQLINVKFYRCS-UHFFFAOYSA-N

Triclosan

5-Chloro-2-(2,4-dichlorophenoxy)phenol Phenol, 5-chloro-2-(2,4-dichlorophenoxy)- 2, 4, 4'-Trichloro-2'-hydroxydiphenylether 2,2'-Oxybis(1',5'-dichlorophenyl-5-chlorophenol) 2,4,4'-TRICHLORO-2'-HYDROXY DIPHENYLETHER 2',4',4-Trichloro-2-hydroxydiphenyl ether 2',4,4'-Trichloro-2-hydroxydiphenyl ether 2,4,4'-Trichloro-2'-hydroxydiphenyl ether 2'-Hydroxy-2,4,4'-trichlorodiphenyl ether 2-Hydroxy-2',4,4'-trichlorodiphenyl ether 3-Chloro-6-(2,4-dichlorophenoxy)phenol 4-Chloro-2-hydroxyphenyl 2,4-dichlorophenyl ether 5-Chloro-2-(2', 4'-dichlorophenoxy) phenol Aquasept Bacti-Stat soap Cansan TCH DIPHENYL ETHER, 2,4,4'-TRICHLORO-2'-HYDROXY- Irgacare MP Irgacide LP 10 Irgaguard B 1000 Irgaguard B 1325 Irgasan Irgasan CH 3565 Irgasan DP 30 Irgasan DP 300 Irgasan DP 3000 Irgasan DP 400 Irgasan PE 30 Irgasan PG 60 Microban Additive B Microban B Oletron Phenol, 5-chloro-2-(2,4-dichlorophenoxy) Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-, dihydrogen phosphate Sanitized XTX Sapoderm SterZac Tinosan AM 100 Tinosan AM 110 TRICLOSAM Ultra Fresh NM 100 Ultrafresh NM-V 2 Vinyzene DP 7000 Yujiexin Zilesan UW

DTXSID5032498

518-82-1

RHMXXJGYXNZAPX-UHFFFAOYSA-N

Emodin

9,10-Anthracenedione, 1,3,8-trihydroxy-6-methyl- 1,3,8-trihidroxi-6-metilantraquinona 1,3,8-Trihydroxy-6-methyl-9,10-anthraquinone 1,3,8-Trihydroxy-6-methylanthrachinon 1,3,8-trihydroxy-6-methylanthraquinone 1,6,8-Trihydroxy-3-methylanthraquinone 3-Methyl-1,6,8-trihydroxyanthraquinone 4,5,7-Trihydroxy-2-methylanthraquinone Anthraquinone, 1,3,8-trihydroxy-6-methyl- Frangula emodin Frangulic acid NSC 408120 NSC 622947 Rheum emodin Schuttgelb

DTXSID5025231

10537-47-0

MZOPWQKISXCCTP-UHFFFAOYSA-N

Malonoben

DTXSID1042106

UBERON:0005620

UBERON primary palate

UBERON:0001716

UBERON secondary palate

GO:0005623

GO cell

PR:000014841

PR sonic hedgehog protein

PR:000008026

PR zinc finger protein GLI1

PR:000008027

PR zinc finger protein GLI2

HP:0000175

HP Cleft palate

MP:0005170

MP cleft upper lip

MP:0009888

MP palatal shelves fail to meet at midline

GO:0008283

GO cell proliferation

GO:0019932

GO second-messenger-mediated signaling

GO:0006915

GO apoptotic process

GO:0010467

GO gene expression

GO:0000060

GO protein import into nucleus, translocation

WIKI increased

WIKI decreased

2,4-Dinitrophenol

2016-11-29T18:42:27

Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone

2020-11-12T17:59:28

Carbonyl cyanide m-chlorophenyl hydrazone

2020-11-12T17:59:47

Pentachlorophenol

2020-11-12T17:59:12

Triclosan

2020-11-12T18:00:07

Emodin

2020-11-20T13:48:58

Malonoben

2020-11-27T14:43:47

WikiUser_28

Vertebrates

WCS_7955

common ecological species zebrafish

WCS_9606

common toxicological species human

10116

NCBI rat

10090

NCBI mouse

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

6239

NCBI Caenorhabditis elegans

Increase, Orofacial clefting

orofacial cleft

Individual

Orofacial clefts (OFC) are one of the most common birth defects. Orofacial clefts are commonly divided on the anatomy they affect by clefts of the lip and/or palate (CL/P) and those of the palate only (CPO) (Murray 2002). Clefts can also be classified as either syndromic when they occur with other physical or developmental anomalies or nonsydromic in the absence of other symptoms (Stanier and Moore 2004). Like most births, the etiology of OFCs are complex and include a combination of genetic and chemical factors (Lipinski and Bushman 2010, Heyne, Melberg et al. 2015). Orofacial development is tightly regulated by multiple signaling pathways and genes including: fibroblast growth factors (Fgfs), Sonic Hedgehog (shh), bone morphogenic protein (Bmp), transforming growth factor beta (Tgf- β) and transcription factors including Dlx, Pitx, Hox, Gli and T-box (Stanier and Moore 2004). Orofacial development requires precise cell migration, growth, differentiation and apoptosis to create the needed orofacial structures from the oropharyngeal membrane (Jugessur and Murray 2005).  During the sixth week of human embryogenesis the medial nasal prominences merge to form the primary palate and the upper lip. The mandibular prominences merge across the midline to produce the lower jaw and lip. Development of the secondary palate begins in the sixth week where the palatal shelves extend internally to the maxillary processes. The shelves then elevate above the tongue and grow towards each other until contact occurs. During weeks 7-8 the medial edges of the palatal shelves fuse through as series of epithelial-mesenchyme transition (EMT) and apoptosis(Jugessur and Murray 2005, Zhang, Tian et al. 2016). Disruption to the complex processes required for proper orofacial development can occur both through genetic factors and environmental (i.e. chemical) exposure by causing disruption to one or multiple steps of orofacial development resulting in OFC.

<ul> <li style="text-align:justify">OFC can be visually observed both in humans and in animals. It can be classified by which tissues (e.g.cleft lip and palate) are effected and its’ severity (complete/incomplete, unilateral/bilateral). Techniques such as the revised Smith-modified Kernahan ‘Y’ classification can be used describe the type, location, and extent of OFC deformities (Khan, Ullah et al. 2013). </li> </ul>

<ul> <li style="text-align:justify">Sex- OFC can occur for all sexes. Differences in incidence between males and females have been found however a clear understanding of what causes this difference is not understood. Cleft lip with or without cleft palate is more common in males while cleft palate only is more common for females (Barbosa Martelli, Machado et al. 2012).</li> <li style="text-align:justify">Life stages- Orofacial development and any disruption leading to clefting occurs early in embryonic development. This begins between the 6th and 12th week of pregnancy in humans and between day 10.0 and 15 in mice (Okuhara and Iseki 2012). </li> <li style="text-align:justify">Taxonomic- Orofacial development occurs in all vertebrates.  </li> </ul>

Not Specified Unspecific

High

Embryo

Not Specified

Barbosa Martelli, D. R., R. A. Machado, M. S. Oliveira Swerts, L. A. Mendes Rodrigues, S. N. de Aquino and H. M. Júnior (2012). "Non sindromic cleft lip and palate: relationship between sex and clinical extension." Brazilian Journal of Otorhinolaryngology 78(5): 116-120. Heyne, G. W., C. G. Melberg, P. Doroodchi, K. F. Parins, H. W. Kietzman, J. L. Everson, L. J. Ansen-Wilson and R. J. Lipinski (2015). "Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate." PLoS One 10(3): e0120517. Jugessur, A. and J. C. Murray (2005). "Orofacial clefting: recent insights into a complex trait." Curr Opin Genet Dev 15(3): 270-278. Khan, M., H. Ullah, S. Naz, T. Iqbal, T. Ullah, M. Tahir and O. Ullah (2013). "A revised classification of the cleft lip and palate." Can J Plast Surg 21(1): 48-50. Lipinski, R. J. and W. Bushman (2010). "Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening." Toxicol In Vitro 24(5): 1404-1409. Murray, J. C. (2002). "Gene/environment causes of cleft lip and/or palate." Clin Genet 61(4): 248-256. Okuhara, S. and S. Iseki (2012). "Epithelial integrity in palatal shelf elevation." Japanese Dental Science Review 48(1): 18-22. Stanier, P. and G. E. Moore (2004). "Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts." Hum Mol Genet 13 Spec No 1: R73-81. Zhang, J., X.-J. Tian and J. Xing (2016). "Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks." Journal of clinical medicine 5(4): 41. AOPWiki 2022-07-27T09:34:49

2025-04-03T13:10:36

Decrease, facial prominence outgrowth

Tissue

For humans and other mammals, the palate serves as a barrier between the mouth and nasal cavity allowing for simultaneous breathing and eating. The palate consists of an anterior bony hard palate and a posterior muscular soft palate that closes the nasal airways for swallowing and directs airflow to help in generation of speech (Li, Lan et al. 2017). The palate is divided into primary and secondary portions. The primary palate contains the philtrum and the upper incisor region anterior to the incisive foramen while the secondary palate encompasses the remainder of the hard and soft palate (Bush and Jiang 2012).  The secondary palate arises during embryonic development as bilateral outgrowths from the maxillary processes. In mammals, these shelves grow first vertically down the tongue before elevating to a position above the dorsum of the tongue where the two shelves meet and fuse to form an intact palate (Ferguson 1988).

<ul> <li style="text-align:justify">Palatal shelf outgrowth can be quantified using imaging techniques such as 3D CT scans during development. Insufficient palatal outgrowth will result in cleft palate. The distance between palatal shelves corelating with outgrowth can be measured and quantified for these individuals. </li> <li style="text-align:justify">Embryos can be dissected and the facial prominences measured (Rice, Connor et al. 2006).</li> </ul>

<ul> <li style="text-align:justify">Sex- There are no known differences in palatal outgrowth in terms of sex. </li> <li style="text-align:justify">Life stages- The palate develops early in embryonic development. This begins between the 6th and 12th week of pregnancy in humans and between day 10.0 and 15 in mice (Okuhara and Iseki 2012). </li> <li style="text-align:justify">Taxonomic- Palatal outgrowth is required for proper palate formation in all vertebrates. </li> </ul>

Not Specified Unspecific

High

Embryo

High

Bush, J. O. and R. Jiang (2012). "Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development." Development 139(2): 231-243. Ferguson, M. W. (1988). "Palate development." Development 103 Suppl: 41-60. Li, C., Y. Lan and R. Jiang (2017). "Molecular and Cellular Mechanisms of Palate Development." J Dent Res 96(11): 1184-1191. Okuhara, S. and S. Iseki (2012). "Epithelial integrity in palatal shelf elevation." Japanese Dental Science Review 48(1): 18-22. Rice, R., E. Connor and D. P. C. Rice (2006). "Expression patterns of Hedgehog signalling pathway members during mouse palate development." Gene Expression Patterns 6(2): 206-212. AOPWiki 2022-07-27T09:10:52

2025-04-03T13:05:05

Decrease, Cell proliferation

Cellular

Decreased cell proliferation describes the outcome of reduced cell division and cell growth. Cell proliferation is considered the main mechanism of tissue and organismal growth (Conlon 1999). Decreased cell proliferation has been associated with abnormal growth-factor signaling and cellular energy depletion (DeBerardinis 2008).

Multiple types of in vitro bioassays can be used to measure this key event: <ul> <li>ToxCast high-throughput screening bioassays such as “BSK_3C_Proliferation”, “BSK_CASM3C_Proliferation” and “BSK_SAg_Proliferation” can be used to measure cell proliferation status.</li> <li>Commercially available methods such as the well-established 5-bromo-2’-deoxyuridine (BrdU) (Raza 1985; Muir 1990) or 5-ethynyl-2’-deoxyuridine (EdU) assay. Both assays measure DNA synthesis in dividing cells to indicate proliferation status.</li> </ul>

Taxonomic applicability domain This key event is in general applicable to all eukaryotes, as most organisms are known to use cell proliferation to achieve growth.   Life stage applicability domain This key event is in general applicable to all life stages. As cell proliferation not only occurs in developing organisms, but also in adults.   Sex applicability domain This key event is sex-unspecific, as both genders use the same cell proliferation mechanisms.

CL:0000000

CL cell

High Unspecific

High

Embryo

High

Juvenile

High High High High

Conlon I, Raff M. 1999. Size control in animal development. Cell 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. 2008. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism 7:11-20. DOI: <a href="https://doi.org/10.1016/j.cmet.2007.10.002">https://doi.org/10.1016/j.cmet.2007.10.002</a>. Muir D, Varon S, Manthorpe M. 1990. An enzyme-linked immunosorbent assay for bromodeoxyuridine incorporation using fixed microcultures. Analytical Biochemistry 185:377-382. DOI: <a href="https://doi.org/10.1016/0003-2697(90)90310-6">https://doi.org/10.1016/0003-2697(90)90310-6</a>. Raza A, Spiridonidis C, Ucar K, Mayers G, Bankert R, Preisler HD. 1985. Double labeling of S-phase murine cells with bromodeoxyuridine and a second DNA-specific probe. Cancer Research 45:2283-2287. AOPWiki 2020-11-12T17:57:08

2020-12-07T06:55:47

Decrease, Sonic Hedgehog second messenger production

Decrease, SHH second messenger production

Cellular

During normal Sonic Hedgehog (SHH) signaling, GLI target gene expression regulates several other signaling pathways. Expression of FOXF1 and FOXL1 upregulate BMP4, BMP 2, and FGF10 in the mesenchyme (Katoh and Katoh 2009, Lan and Jiang 2009). Induction of FGF10 in the mesenchyme is able to induce SHH in the adjacent epithelium via a positive feedback loop with FGFR2 (Cobourne and Green 2012). SHH signaling also upregulates BCL2 and CFLAR to promote cell survival (Katoh and Katoh 2009).

<ul> <li style="text-align:justify">Changes in gene expression can be measured using serial analysis of gene expression (SAGE), rapid analysis of gene expression (RAGE), RT-PCR, Northern/Southern blotting, differential display, and DNA microarray assay (Kirby, Heath et al. 2007).</li> <li style="text-align:justify">RNA in situ hybridization can be used to determine sites of gene expression (Nouri-Aria 2008, Abler, Mansour et al. 2009)</li> <li style="text-align:justify">Antibody staining of tissue sections can be used to determine location and amounts of BMP4, BMP2, FGF10</li> </ul>

<ul> <li style="text-align:justify">Sex- Secondary messenger production of the SHH pathway is present in both male and females and differences in gene expression has not been demonstrated.   </li> <li style="text-align:justify">Life stages- The Hedgehog pathway is a major pathway in embryonic development. </li> <li style="text-align:justify">Taxonomic-HH signalling, and its’ secondary messenger production is present in vertebrates and some invertebrates including flies (Denef, Neubüser et al. 2000, Huangfu and Anderson 2005)  </li> </ul>

CL:0000000

CL cell

Not Specified Unspecific

Not Specified

Embryo

Not Specified

Abler, L. L., S. L. Mansour and X. Sun (2009). "Conditional gene inactivation reveals roles for Fgf10 and Fgfr2 in establishing a normal pattern of epithelial branching in the mouse lung." Dev Dyn 238(8): 1999-2013. Cobourne, M. T. and J. B. Green (2012). "Hedgehog signalling in development of the secondary palate." Front Oral Biol 16: 52-59. Denef, N., D. Neubüser, L. Perez and S. M. Cohen (2000). "Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened." Cell 102(4): 521-531. Huangfu, D. and K. V. Anderson (2005). "Cilia and Hedgehog responsiveness in the mouse." Proc Natl Acad Sci U S A 102(32): 11325-11330. Katoh, Y. and M. Katoh (2009). "Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation." Curr Mol Med 9(7): 873-886. Kirby, J., P. R. Heath, P. J. Shaw and F. C. Hamdy (2007). Gene Expression Assays. Advances in Clinical Chemistry, Elsevier. 44: 247-292. Lan, Y. and R. Jiang (2009). "Sonic hedgehog signaling regulates reciprocal epithelial-mesenchymal interactions controlling palatal outgrowth." Development 136(8): 1387-1396. Nouri-Aria, K. T. (2008). "In situ Hybridization." Methods Mol Med 138: 331-347.   AOPWiki 2022-08-12T10:33:39

2023-03-22T12:09:35

Apoptosis

Cellular

Apoptosis, the process of programmed cell death, is characterized by distinct morphology with DNA fragmentation and energy dependency [Elmore, 2007]. Apoptosis, also called “physiological cell death”, is involved in cell turnover, physiological involution, and atrophy of various tissues and organs [Kerr et al., 1972]. The formation of apoptotic bodies involves marked condensation of both nucleus and cytoplasm, nuclear fragmentation, and separation of protuberances [Kerr et al., 1972]. Apoptosis is characterized by DNA ladder and chromatin condensation. Several stimuli such as hypoxia, nucleotides deprivation, chemotherapeutical drugs, DNA damage, and mitotic spindle damage induce p53 activation, leading to p21 activation and cell cycle arrest [Pucci et al., 2000]. The SAHA or TSA treatment on neonatal human dermal fibroblasts (NHDFs) for 24 or 72 hrs inhibited proliferation of the NHDF cells [Glaser et al., 2003]. Considering that the acetylation of histone H4 was increased by the treatment of SAHA for 4 hrs, histone deacetylase inhibition may be involved in the inhibition of the cell proliferation [Glaser et al., 2003]. The impaired proliferation was observed in HDAC1-/- ES cells, which was rescued with the reintroduction of HDAC1 [Zupkovitz et al., 2010]. An AOP focuses existes on p21 pathway leading to apoptosis, however, alternative pathways such as NF-kappaB signaling pathways may be involved in the apoptosis of spermatocytes [Wang et al., 2017]. Apoptosis is defined as a programmed cell death.  A decrease in apoptosis or a resistance to cell death is noted is described as a hallmark of cancer by Hanahan et al. It is widely admitted as an essential step in tumor proliferation (Adams, Lowe).  Apoptosis occurs after activation of a number of intrinsic and extrinsic signals which activate the protease caspase system which in turn activates the destruction of the cell.    In mammals, the foetal ovary produces hundreds of thousands of oocytes. But most of them die before birth due to apoptosis (Kaur, S., & Kurokawa, M., 2023). The apoptotic process has a specific pattern at different stages: in foetal ovaries, the majority of apoptotic activity was found in germ cells, whereas in adult quiescent cortical follicles, apoptosis occurred from both granulosa and oocyte cells. The oocyte has been shown to be the one that triggers the apoptotic process and causes follicular atresia (Jin, X., et al. (2011). In humans, the primordial follicles' ovarian endowment is formed throughout foetal development. Apoptotic cell death, which is carried out with the assistance of multiple players and routes conserved from worms to humans, depletes this endowment by at least two-thirds prior to birth. As of right now, apoptosis has been linked to atresia, oocyte loss/selection, folliculogenesis, and oogenesis (Hussein MR, 2005) The Bcl-2 is a protein family suppressing apoptosis by binding and inhibiting two proapoptotic proteins (Bax and Bak) and transferring them to the mitochondrial outer membrane. In the absence of inhibition by Bcl2, Bax and Bak destroy the mitochondrial membrane and releases proapoptotic signaling proteins, such as cytochrome c which activated the caspase system. An increased expression of these antiapoptotic proteins (Bcl-2, Bcl-xL) occurs in cancer (Hanahan, Adams, Lowe). Several others pathways such as the loss of TP53 tumor suppressor function, or the increase of survival signals (Igf1/2), or decrease of proapoptotic factors (Bax, Bim, Puma) can also increase tumor growth (Hanahan, Juntilla). In breast cancer a decrease in apoptosis and a resistance to cell death has been described thoroughly, especially using a dysregulation of the Bcl2 system or TP53 (Parton, Williams, Shahbandi).

Apoptosis is characterized by many morphological and biochemical changes such as homogenous condensation of chromatin to one side or the periphery of the nuclei, membrane blebbing and formation of apoptotic bodies with fragmented nuclei, DNA fragmentation, enzymatic activation of pro-caspases, or phosphatidylserine translocation that can be measured using electron and cytochemical optical microscopy, proteomic and genomic methods, and spectroscopic techniques [Archana et al., 2013; Martinez et al., 2010; Taatjes et al., 2008; Yasuhara et al., 2003]. ・DNA fragmentation can be quantified with comet assay using electrophoresis, where the tail length, head size, tail intensity, and head intensity of the comet are measured [Yasuhara et al., 2003]. ・The apoptosis is detected with the expression alteration of procaspases 7 and 3 by Western blotting using antibodies [Parajuli et al., 2014]. ・The apoptosis is measured with down-regulation of anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, or cIAP1) [Parajuli et al., 2014]. ・Apoptotic nucleosomes are detected using Cell Death Detection ELISA kit, which was calculated as absorbance subtraction at 405 nm and 490 nm [Parajuli et al., 2014]. ・Cleavage of PARP is detected with Western blotting [Parajuli et al., 2014]. ・Caspase-3 and caspase-9 activity is measured with the enzyme-catalyzed release of p-nitroanilide (pNA) and quantified at 405 nm [Wu et al., 2016]. ・Apoptosis is measured with Annexin V-FITC probes, and the relative percentage of Annexin V-FITC-positive/PI-negative cells is analyzed by flow cytometry [Wu et al., 2016]. ・Apoptosis is detected with the Terminal dUTP Nick End-Labeling (TUNEL) method to assay the endonuclease cleavage products by enzymatically end-labeling the DNA strand breaks [Kressel and Groscurth, 1994]. ・For the detection of apoptosis, the testes are fixed in neutral buffered formalin and embedded in paraffin. Germ cell death is visualized in testis sections by Terminal dUTP Nick End-Labeling (TUNEL) staining method [Wade et al., 2008]. The incidence of TUNEL-positive cells is expressed as the number of positive cells per tubule examined for one entire testis section per animal [Wade et al., 2008]

・Apoptosis is induced in human prostate cancer cell lines (Homo sapiens) [Parajuli et al., 2014]. ・Apoptosis occurs in B6C3F1 mouse (Mus musculus) [Elmore, 2007]. ・Apoptosis occurs in Sprague-Dawley rat (Rattus norvegicus) [Elmore, 2007]. ・Apoptosis occurs in the nematode (Caenorhabditis elegans) [Elmore, 2007]. <ul> <li>Apoptosis occurs in breast cancer cells, human and mouse (Parton)</li> <li style="text-align:justify">Apoptosis applicable to fishes, hence be used to study as models (dos Santos, N. M., et al. (2008).</li> <li style="text-align:justify">Apoptosis in humans and baboon ovaries (Kugu, K., et al. (1998)</li> <li style="text-align:justify">Apoptosis in amphibians during metamorphosis (Ishizuya-Oka, A., et al. (2010).</li> <li style="text-align:justify">Apoptosis in Drosophila melanogaster (Steller, H. (2008)</li> <li style="text-align:justify">Apoptosis is a highly conserved and essential process across a broad taxonomic range, from unicellular eukaryotes to complex multicellular animals, it is also evident in metazoans (Suraweera, C. D., et al. (2022).</li> <li> Sex Applicability: Both sexes. Apoptosis occurs in male and female systems (e.g., oocyte and sperm cell turnover). </li> <li> Life Stage Applicability: All stages. Especially critical during embryonic development and in maintaining adult tissue homeostasis. </li> </ul>

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Unspecific

High

Not Otherwise Specified

High High High High

Archana, M. et al. (2013), "Various methods available for detection of apoptotic cells", Indian J Cancer 50:274-283 Elmore, S. (2007), "Apoptosis: a review of programmed cell death", Toxicol Pathol 35:495-516 Glaser, K.B. et al. (2003), "Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines", Mol Cancer Ther 2:151-163 Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257 Kressel, M. and Groscurth, P. (1994), "Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA", Cell Tissue Res 278:549-556 Martinez, M.M. et al. (2010), "Detection of apoptosis: A review of conventioinal and novel techniques", Anal Methods 2:996-1004 Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313 Pucci, B. et al. (2000), "Cell cycle and apoptosis", Neoplasia 2:291-299 Taatjes, D.J. et al. (2008), "Morphological and cytochemical determination of cell death by apoptosis", Histochem Cell Biol 129:33-43 Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831 Wang, C. et al. (2017), "CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways", Oncotarget 8:3132-3143 Wu, R. et al. (2016), "microRNA-497 induces apoptosis and suppressed proliferation via the Bcl-2/Bax-caspase9-caspase 3 pathway and cyclin D2 protein in HUVECs", PLoS One 11:e0167052 Yasuhara, S. et al. (2003), "Comparison of comet assay, electron microscopy, and flow cytometry for detection of apoptosis", J Histochem Cytochem 51:873-885 Zupkovitz, G. et al. (2010), "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation", Mol Cell Biol 30:1171-1181   Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230 Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007 Feb 26;26(9):1324-37. doi: 10.1038/sj.onc.1210220. PMID: 17322918; PMCID: PMC2930981. Lowe, S., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004). <a href="https://doi.org/10.1038/nature03098" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/nature03098</a> Parton M, Dowsett M, Smith I. Studies of apoptosis in breast cancer. BMJ. 2001 Jun 23;322(7301):1528-32. doi: 10.1136/bmj.322.7301.1528. PMID: 11420276; PMCID: PMC1120573. Junttila MR, Evan GI. p53--a Jack of all trades but master of none. Nat Rev Cancer. 2009 Nov;9(11):821-9. doi: 10.1038/nrc2728. Epub 2009 Sep 24. PMID: 19776747. Williams MM, Cook RS. Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance? Oncotarget. 2015 Feb 28;6(6):3519-30. doi: 10.18632/oncotarget.2792. PMID: 25784482; PMCID: PMC4414133. Shahbandi A, Nguyen HD, Jackson JG. TP53 Mutations and Outcomes in Breast Cancer: Reading beyond the Headlines. Trends Cancer. 2020 Feb;6(2):98-110. doi: 10.1016/j.trecan.2020.01.007. Epub 2020 Feb 5. PMID: 32061310; PMCID: PMC7931175. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230 Adams JM, Cory S. The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 2007 Feb 26;26(9):1324-37. doi: 10.1038/sj.onc.1210220. PMID: 17322918; PMCID: PMC2930981. Lowe, S., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004). <a href="https://doi.org/10.1038/nature03098" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/nature03098</a> Parton M, Dowsett M, Smith I. Studies of apoptosis in breast cancer. BMJ. 2001 Jun 23;322(7301):1528-32. doi: 10.1136/bmj.322.7301.1528. PMID: 11420276; PMCID: PMC1120573. Junttila MR, Evan GI. p53--a Jack of all trades but master of none. Nat Rev Cancer. 2009 Nov;9(11):821-9. doi: 10.1038/nrc2728. Epub 2009 Sep 24. PMID: 19776747. Williams MM, Cook RS. Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance? Oncotarget. 2015 Feb 28;6(6):3519-30. doi: 10.18632/oncotarget.2792. PMID: 25784482; PMCID: PMC4414133. Shahbandi A, Nguyen HD, Jackson JG. TP53 Mutations and Outcomes in Breast Cancer: Reading beyond the Headlines. Trends Cancer. 2020 Feb;6(2):98-110. doi: 10.1016/j.trecan.2020.01.007. Epub 2020 Feb 5. PMID: 32061310; PMCID: PMC7931175.   Parton M, Dowsett M, Smith I. Studies of apoptosis in breast cancer. BMJ. 2001 Jun 23;322(7301):1528-32. doi: 10.1136/bmj.322.7301.1528. PMID: 11420276; PMCID: PMC1120573.   <ul> <li>Kaur S, Kurokawa M. Regulation of Oocyte Apoptosis: A View from Gene Knockout Mice. Int J Mol Sci. 2023;24(2).</li> <li>Jin X, Xiao LJ, Zhang XS, Liu YX. Apotosis in ovary. Front Biosci (Schol Ed). 2011;3(2):680-97.</li> <li>Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005;11(2):162-77.</li> <li>dos Santos NM, do Vale A, Reis MI, Silva MT. Fish and apoptosis: molecules and pathways. Curr Pharm Des. 2008;14(2):148-69.</li> <li>Kugu K, Ratts VS, Piquette GN, Tilly KI, Tao XJ, Martimbeau S, et al. Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary. Cell Death Differ. 1998;5(1):67-76.</li> <li>Ishizuya-Oka A, Hasebe T, Shi YB. Apoptosis in amphibian organs during metamorphosis. Apoptosis. 2010;15(3):350-64.</li> <li>Steller H. Regulation of apoptosis in Drosophila. Cell Death & Differentiation. 2008;15(7):1132-8.</li> <li>Suraweera CD, Banjara S, Hinds MG, Kvansakul M. Metazoans and Intrinsic Apoptosis: An Evolutionary Analysis of the Bcl-2 Family. International Journal of Molecular Sciences. 2022;23(7):3691.</li> </ul> AOPWiki 2017-02-07T13:21:50

2025-05-31T08:50:09

Decrease, GLI1/2 target gene expression

Cellular

The Glioma-associated onocogene (GLI) family of zinc finger transcription factors (Gli1, Gli2, Gli3) are the primarily downstream effectors of the Hedgehog (HH) signaling cascade. When HH ligand binds to Patched (PTCH), its’ inhibition on SMO is relieved. SMO is then able to accumulate to the tip of primary cilium in its’ active form (Corbit, Aanstad et al. 2005, Rohatgi, Milenkovic et al. 2007, Kim, Kato et al. 2009). SMO causes the GLI family to become dislodged from their complex with the negative regulator of HH signaling, Suppressor of Fused (Sufu) (Kogerman, Grimm et al. 1999, Pearse, Collier et al. 1999, Stone, Murone et al. 1999, Tukachinsky, Lopez et al. 2010). The GLI-Sufu complex maintains retention of Gli in the cytosol allowing for exposure to phosphorylation via protein kinase A (PKA) which inhibits downstream signal transduction  (Tuson, He et al. 2011). When SMO is activated the GLI2/3-Sufu complex is dismantled allowing for retrograde transport of GLI back into the nucleus (Kim, Kato et al. 2009). Following translocation into the nucleus, the GLI family of transcription factors initiates transcription of a variety of genes. The genes transcribed by activation of the SHH pathway are cell type dependent but commonly include GLI1 and PTCH1 (Stamataki, Ulloa et al. 2005, Cohen, Kicheva et al. 2015, Tickle and Towers 2017). During development of the neural tube SHH is associated with NKX6.1, OLIG2, NKX2.2 and the FOXA2 genes (Vokes, Ji et al. 2007, Kutejova, Sasai et al. 2016). Other genes have are known targets of GLI transcription include PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLA, FOXF1, FOXFL1, PRDM1, JAG2, GREM1, FOXB2, FOXA2, FOXB2, FOXC1, FOXC2, FOXD1, FOXE1, FOXF1, FOXF2, FOXL1 and follistatin (Katoh and Katoh 2009, Everson, Fink et al. 2017).

•    Sex- The GLI family of transcription factors is present in both male and females and differences in gene expression have not been demonstrated.    •    Life stages- The Hedgehog pathway with the main transcription factors of GLI1/2 can be active during all stages of life. It is a major pathway in embryonic development. Aberrant activation of HH signaling is known to cause cancer (Dahmane, Lee et al. 1997, Kimura, Stephen et al. 2005). For these reasons all stages of life are of relevance. •    Taxonomic-HH signaling including the GLI transcription factors is present in vertebrates and some invertebrates including flies (Denef, Neubüser et al. 2000, Huangfu and Anderson 2005)

CL:0000000

CL cell

Not Specified Unspecific

Not Specified

All life stages

Cohen, M., A. Kicheva, A. Ribeiro, R. Blassberg, K. M. Page, C. P. Barnes and J. Briscoe (2015). "Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms." Nature Communications 6(1): 6709. Corbit, K. C., P. Aanstad, V. Singla, A. R. Norman, D. Y. R. Stainier and J. F. Reiter (2005). "Vertebrate Smoothened functions at the primary cilium." Nature 437(7061): 1018-1021. Dahmane, N., J. Lee, P. Robins, P. Heller and A. Ruiz i Altaba (1997). "Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours." Nature 389(6653): 876-881. Denef, N., D. Neubüser, L. Perez and S. M. Cohen (2000). "Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened." Cell 102(4): 521-531. Everson, J. L., D. M. Fink, J. W. Yoon, E. J. Leslie, H. W. Kietzman, L. J. Ansen-Wilson, H. M. Chung, D. O. Walterhouse, M. L. Marazita and R. J. Lipinski (2017). "Sonic hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis." Development 144(11): 2082-2091. Huangfu, D. and K. V. Anderson (2005). "Cilia and Hedgehog responsiveness in the mouse." Proc Natl Acad Sci U S A 102(32): 11325-11330. Katoh, Y. and M. Katoh (2009). "Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation." Curr Mol Med 9(7): 873-886. Kim, J., M. Kato and P. A. Beachy (2009). "Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus." Proc Natl Acad Sci U S A 106(51): 21666-21671. Kimura, H., D. Stephen, A. Joyner and T. Curran (2005). "Gli1 is important for medulloblastoma formation in Ptc1+/- mice." Oncogene 24(25): 4026-4036. Kirby, J., P. R. Heath, P. J. Shaw and F. C. Hamdy (2007). Gene Expression Assays. Advances in Clinical Chemistry, Elsevier. 44: 247-292. Kogerman, P., T. Grimm, L. Kogerman, D. Krause, A. B. Undén, B. Sandstedt, R. Toftgård and P. G. Zaphiropoulos (1999). "Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1." Nat Cell Biol 1(5): 312-319. Kutejova, E., N. Sasai, A. Shah, M. Gouti and J. Briscoe (2016). "Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs." Dev Cell 36(6): 639-653. Pearse, R. V., 2nd, L. S. Collier, M. P. Scott and C. J. Tabin (1999). "Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators." Dev Biol 212(2): 323-336. Rohatgi, R., L. Milenkovic and M. P. Scott (2007). "Patched1 regulates hedgehog signaling at the primary cilium." Science 317(5836): 372-376. Stamataki, D., F. Ulloa, S. V. Tsoni, A. Mynett and J. Briscoe (2005). "A gradient of Gli activity mediates graded Sonic Hedgehog signaling in the neural tube." Genes Dev 19(5): 626-641. Stone, D. M., M. Murone, S. Luoh, W. Ye, M. P. Armanini, A. Gurney, H. Phillips, J. Brush, A. Goddard, F. J. de Sauvage and A. Rosenthal (1999). "Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli." J Cell Sci 112 ( Pt 23): 4437-4448. Tickle, C. and M. Towers (2017). "Sonic Hedgehog Signaling in Limb Development." Front Cell Dev Biol 5: 14. Tukachinsky, H., L. V. Lopez and A. Salic (2010). "A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes." J Cell Biol 191(2): 415-428. Tuson, M., M. He and K. V. Anderson (2011). "Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube." Development 138(22): 4921-4930. Vokes, S. A., H. Ji, S. McCuine, T. Tenzen, S. Giles, S. Zhong, W. J. Longabaugh, E. H. Davidson, W. H. Wong and A. P. McMahon (2007). "Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning." Development 134(10): 1977-1989. AOPWiki 2022-07-25T10:54:25

2025-04-02T11:24:48

Decrease, GLI1/2 translocation to nucleus

Decrease, GLI1/2 translocation

Molecular

The Glioma-associated onocogene (Gli) family of zinc finger transcription factors (Gli1, Gli2, Gli3) are the primarily downstream effectors of the Hedgehog (HH) signaling cascade. When HH ligand binds to Patched (PTCH), its’ inhibition on SMO is relieved. SMO this then able to accumulate to the tip of primary cilium in its’ active form (Corbit, Aanstad et al. 2005, Rohatgi, Milenkovic et al. 2007, Kim, Kato et al. 2009). SMO causes the GLI family to become dislodged from their complex with the negative regulator of HH signaling, Suppressor of Fused (Sufu) (Kogerman, Grimm et al. 1999, Pearse, Collier et al. 1999, Stone, Murone et al. 1999, Tukachinsky, Lopez et al. 2010). The GLI-Sufu complex maintains retention of Gli in the cytosol allowing for exposure to phosphorylation via protein kinase A (PKA) which inhibits downstream signal transduction  (Tuson, He et al. 2011). When SMO is activated the GLI2/3-Sufu complex is dismantled allowing for retrograde transport of GLI back into the nucleus (Kim, Kato et al. 2009). The GLI family is found in both a long activator form (GliA) or a proteolytically cleaved repressor form (GliR). Current understanding is that Gli3 functions primarily as a repressor while Gli1 and Gli2 function mainly as activators of the pathway and that recruitment of SMO to the cilium leads to a increase in the ratio of GliA:GliR (Hui and Angers 2011, Liu 2016).

<ul> <li style="text-align:justify">A nuclear translocation assay (NTA) can be applied to determine the amount of protein that translocate into the nucleus (Dixon and Lim 2010). </li> <li style="text-align:justify">Nuclear protein extracts can be analysed to determine if the protein of interest (GLI1/2) translocated to the nucleus (Kim, Kato et al. 2009). </li> <li style="text-align:justify">Immunofluorescence and microscopy can be used to determine how much of a protein has translocated to the nucleus. Primary antibodies can be used to tag GLI in combination with a secondary stain for the nucleus (Blotta, Jakubikova et al. 2012). </li> </ul>

<ul> <li style="text-align:justify">Sex- The Gli family of transcription factors is present in both male and females and differences in activation or antagonism between sex have not been demonstrated.  </li> <li style="text-align:justify">Life stages- The Hedgehog pathway is a major pathway in embryonic development. Aberrant activation of HH signalling is known to cause cancer (Dahmane, Lee et al. 1997, Kimura, Stephen et al. 2005). For these reasons all stages of life are of relevance. </li> <li style="text-align:justify">Taxonomic-HH signalling including the Gli transcription factors is present in vertebrates and some invertebrates inclubind flies (Denef, Neubüser et al. 2000, Huangfu and Anderson 2005)  </li> </ul>

CL:0000000

CL cell

Not Specified Unspecific

High

Embryo

High

All life stages

Blotta, S., J. Jakubikova, T. Calimeri, A. M. Roccaro, N. Amodio, A. K. Azab, U. Foresta, C. S. Mitsiades, M. Rossi, K. Todoerti, S. Molica, F. Morabito, A. Neri, P. Tagliaferri, P. Tassone, K. C. Anderson and N. C. Munshi (2012). "Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma." Blood 120(25): 5002-5013. Corbit, K. C., P. Aanstad, V. Singla, A. R. Norman, D. Y. R. Stainier and J. F. Reiter (2005). "Vertebrate Smoothened functions at the primary cilium." Nature 437(7061): 1018-1021. Dahmane, N., J. Lee, P. Robins, P. Heller and A. Ruiz i Altaba (1997). "Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours." Nature 389(6653): 876-881. Denef, N., D. Neubüser, L. Perez and S. M. Cohen (2000). "Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened." Cell 102(4): 521-531. Dixon, A. S. and C. S. Lim (2010). "The nuclear translocation assay for intracellular protein-protein interactions and its application to the Bcr coiled-coil domain." Biotechniques 49(1): 519-524. Huangfu, D. and K. V. Anderson (2005). "Cilia and Hedgehog responsiveness in the mouse." Proc Natl Acad Sci U S A 102(32): 11325-11330. Hui, C. C. and S. Angers (2011). "Gli proteins in development and disease." Annu Rev Cell Dev Biol 27: 513-537. Kim, J., M. Kato and P. A. Beachy (2009). "Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus." Proc Natl Acad Sci U S A 106(51): 21666-21671. Kimura, H., D. Stephen, A. Joyner and T. Curran (2005). "Gli1 is important for medulloblastoma formation in Ptc1+/- mice." Oncogene 24(25): 4026-4036. Kogerman, P., T. Grimm, L. Kogerman, D. Krause, A. B. Undén, B. Sandstedt, R. Toftgård and P. G. Zaphiropoulos (1999). "Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1." Nat Cell Biol 1(5): 312-319. Liu, K. J. (2016). "Craniofacial Ciliopathies and the Interpretation of Hedgehog Signal Transduction." PLoS Genet 12(12): e1006460. Pearse, R. V., 2nd, L. S. Collier, M. P. Scott and C. J. Tabin (1999). "Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators." Dev Biol 212(2): 323-336. Rohatgi, R., L. Milenkovic and M. P. Scott (2007). "Patched1 regulates hedgehog signaling at the primary cilium." Science 317(5836): 372-376. Stone, D. M., M. Murone, S. Luoh, W. Ye, M. P. Armanini, A. Gurney, H. Phillips, J. Brush, A. Goddard, F. J. de Sauvage and A. Rosenthal (1999). "Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli." J Cell Sci 112 ( Pt 23): 4437-4448. Tukachinsky, H., L. V. Lopez and A. Salic (2010). "A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes." J Cell Biol 191(2): 415-428. Tuson, M., M. He and K. V. Anderson (2011). "Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube." Development 138(22): 4921-4930.   AOPWiki 2022-07-15T11:06:59

2022-10-28T15:22:48

Decrease, cholesterol synthesis leads to orofacial clefting

Decrease, cholesterol synthesis leads to OFC

Jacob Reynolds

Jacob I. Reynolds1 , Brian P. Johnson1,2  1Department of Biomedical Engineering, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 2Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI Judy Choi

BY-SA

Under Development

1.101

2.6

OFC is one of the most common birth defects occurring in approximately 1 in 700 live births. The etiology of OFC is poorly understood and is believed to be a combination of genetic and environmental factors. Understanding the genetic and environmental factors that can lead to OFC is the first step in preventing this birth defect.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

AOPWiki 2023-06-28T08:18:39

2023-08-31T09:40:10