Extensive clinical and experimental research documents the potential for chemical disruption of thyroid hormone (TH) signalling through multiple molecular targets. Perturbation of TH signalling can lead to abnormal brain development, cognitive impairments, and other adverse outcomes in humans and wildlife. To increase chemical safety screening efficiency and reduce vertebrate animal testing, in vitro assays that identify chemical interactions with molecular targets of the thyroid system have been developed and implemented. In the present study, the authors present an adverse outcome pathway (AOP) network to link data derived from in vitro assays that measure chemical interactions with thyroid molecular targets to downstream events and adverse outcomes traditionally derived from in vivo testing. The authors examine the role of new in vitro technologies, in the context of the AOP network, in facilitating consideration of several important regulatory and biological challenges in characterizing chemicals that exert effects through a thyroid mechanism. There is a substantial body of knowledge describing chemical effects on molecular and physiological regulation of TH signalling and associated adverse outcomes. Until recently, few alternative nonanimal assays were available to interrogate chemical effects on TH signalling. With the development of these new tools, screening large libraries of chemicals for interactions with molecular targets of the thyroid is now possible. Measuring early chemical interactions with targets in the thyroid pathway provides a means of linking adverse outcomes, which may be influenced by many biological processes, to a thyroid mechanism. However, the use of in vitro assays beyond chemical screening is complicated by continuing limits in our knowledge of TH signalling in important life stages and tissues, such as during foetal brain development. Nonetheless, the thyroid AOP network provides an ideal tool for defining causal linkages of a chemical exerting thyroid-dependent effects and identifying research needs to quantify these effects in support of regulatory decision making.
Authors: Noyes PD, Friedman KP, Browne P, Haselman JT, Gilbert ME, Hornung MW, Barone S Jr, Crofton KM, Laws SC, Stoker TE, Simmons SO, Tietge JE, Degitz SJ.
; Full Source: Environmental Health Perspectives. 2019 Sep;127(9):95001. doi: 10.1289/EHP5297. Epub 2019 Sep 5.