K. Crofton, M. Gilbert, K. P. Friedman, B. Demeneix, M. S. Marty, R. Zoeller
{"title":"Adverse Outcome Pathway on inhibition of Thyroperoxidase and subsequent adverse neurodevelopmental outcomes in mammals","authors":"K. Crofton, M. Gilbert, K. P. Friedman, B. Demeneix, M. S. Marty, R. Zoeller","doi":"10.1787/EA5AA069-EN","DOIUrl":"https://doi.org/10.1787/EA5AA069-EN","url":null,"abstract":"This AOP describes one adverse outcome that may result from the inhibition of thyroperoxidase (TPO) during mammalian development. Chemical inhibition of TPO results in decreased thyroid hormone (TH) synthesis, and subsequent reduction in circulating concentrations of THs. THs are essential for normal human brain development, both prenatally and postnatally, modulating genes critical for a normal neuroanatomical development, with subsequent effects on neurophysiology, and finally neurological function. Therefore, chemicals that interfere with TH synthesis have the potential to cause TH insufficiency that may result in adverse neurodevelopmental effects in offspring. Herein, we discuss the implications of developmental TPO inhibition for hippocampal anatomy, function, and ultimately neural function. The hippocampus is known to be critically involved in cognitive, emotional, and memory function. The adverse consequences of TH insufficiency depend both on severity and developmental timing, indicating that exposure to TPO inhibitors may produce different effects at different developmental windows of exposure.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"365 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126955791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Adverse Outcome Pathway on binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain","authors":"P. Gong, E. Perkins","doi":"10.1787/9226875E-EN","DOIUrl":"https://doi.org/10.1787/9226875E-EN","url":null,"abstract":"This AOP begins with the interaction of chemicals to the picrotoxin binding site of the ionotropic GABA receptor complex causing blockage of the ion channel. As a result, decrease in inward chloride conductance occurs, followed by a reduction in postsynaptic inhibition, reflected as reduced frequency and amplitude of spontaneous inhibitory postsynaptic current or abolishment of GABA-induced firing action. Consequently, the resistance of excitatory neurons to fire is decreased, resulting in the generation of a large excitatory postsynaptic potential (EPSP) that causes voltage-gated Na+ to open, which results in action potentials. The depolarisation is followed by a period of hyper-polarisation mediated by Ca2+-dependent K+ channels or GABA-activated Cl− influx, which becomes smaller, gradually disappears, and is replaced by a depolarisation known as “paroxysmal depolarizing shift” (PDS). A PDS is an indication of epilepsy at the cellular level and initiates the adverse outcome at the organismal level of epileptic seizure.","PeriodicalId":315932,"journal":{"name":"OECD Series on Adverse Outcome Pathways","volume":"111 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124800411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}