雄激素受体
孕烷X受体
芳香烃受体
法尼甾体X受体
甲状腺
核受体
甲状腺激素受体
不良结局途径
受体
下丘脑-垂体-甲状腺轴
甲状腺激素受体β
不利影响
内科学
内分泌学
激素
化学
不良事件报告系统
医学
激素受体
生物
生物化学
三碘甲状腺素
癌症
计算生物学
转录因子
乳腺癌
基因
作者
Etje Hulzebos,Todd Stedeford,Paul Sterchele,Gregory S. Ladics
标识
DOI:10.1016/j.fct.2024.114784
摘要
Octahydro-tetramethyl-naphthalenyl-ethanone (OTNE) is a synthetic fragrance ingredient. OTNE was evaluated in repeated-dose toxicological studies. Target organs via oral and dermal routes were the liver and skin/liver, respectively. Effects were observed on the thyroid and thyroid hormones, suggesting hypothalamic-pituitary-thyroid axis perturbation. We investigated the molecular initiating event(s) (MIEs), key events (KEs), and adverse outcomes of OTNE-induced thyroid perturbation within an adverse outcome pathway (AOP). Data were generated using new approach methodologies (NAMs) on human, mouse, and/or rat receptors exploring MIEs using in vitro receptor ligand-binding assays for androstane receptor variant 3 (CAR), farnesoid X receptor (FXR), liver X receptor alpha (LXRα), peroxisome proliferator-activated receptors alpha, delta, and gamma (PPARα, δ, and γ), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AhR). These data inform an AOP network where CAR, FXR, and PXR activation serve as MIEs with thyroid perturbation occurring as secondary effects. These data represent a robust evaluation using NAMs for mapping OTNE-induced thyroid effects and identifying activation of receptor-ligand binding as MIEs in lieu of additional in vivo experimentation. These data indicate the observed thyroid effects are secondary to liver effects and the thyroid effects, therefore, should not be the basis for assessing potential OTNE-induced human health hazards.
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