Abstract：
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.
摘要：
八氢-四甲基-萘基-乙酮(OTNE)是一种合成香料成分。在重复剂量毒理学研究中评估了OTNE。通过口服和皮肤途径的靶器官是肝脏和皮肤/肝脏，分别。观察对甲状腺及甲状腺激素的影响,提示下丘脑-垂体-甲状腺轴扰动。我们调查了分子启动事件(MIE)，关键事件(KEs)，和OTNE诱导的甲状腺扰动在不良结局途径（AOP）内的不良结局。数据是使用新的方法方法(NAM)生成的，鼠标,和/或使用雄甾烷受体变体3（CAR）的体外受体配体结合测定法探索MIE的大鼠受体，法尼醇X受体（FXR），肝脏X受体α（LXRα），过氧化物酶体增殖物激活受体α，delta,和伽马(PPARα，δ,和γ)，孕烷X受体（PXR），和芳基烃受体(AhR)。这些数据通知AOP网络，FXR,和PXR激活作为MIE，甲状腺扰动作为次要作用发生。这些数据代表了使用NAM来映射OTNE诱导的甲状腺效应并将受体-配体结合的激活鉴定为MIE来代替另外的体内实验的稳健评估。这些数据表明，观察到的甲状腺效应是继发于肝脏效应和甲状腺效应，因此,不应成为评估OTNE引起的潜在人类健康危害的基础。
