Octamethylcyclotetrasiloxane (D4) lacks endocrine disruptive potential via estrogen pathways

IF 4.8 2区 医学 Q1 TOXICOLOGY
Christopher J. Borgert, Lyle D. Burgoon
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引用次数: 0

Abstract

Octamethylcyclotetrasiloxane (D4) is a volatile, highly lipophilic monomer used to produce silicone polymers found in many consumer products and used widely in industrial applications and processes. Many reviews of the toxicology of D4 conclude that its adverse effects on endocrine-sensitive endpoints occur by a MoA dependent on systemic toxicity rather than one mediated via endocrine activity, but others identify D4 as an estrogenic endocrine disruptive chemical (EDC) based on results of screening-level assays indicating that D4 interacts with ERα and at high doses, affects estrogen-sensitive endpoints in rodents. To resolve these divergent interpretations, we tested two specific hypotheses related to the interaction of D4 with estrogen receptor–alpha subtype (ERα) at the biochemical and molecular levels of biological organization and a third specific hypothesis related to estrogenic and anti-estrogenic pathways at the physiological level. At the physiological level, we used an established WoE methodology to evaluate all data relevant to estrogen agonist and antagonist activity of D4 by examining its effects on ERα-relevant endpoints in rodent toxicology studies. At the biochemical level, we calculated whether D4 could produce a functionally significant change in the ERα occupancy by 17β-estradiol (E2) using equations well-established in pharmacology. For these calculations, we used data on the potency and kinetics of D4 from studies in rats as well as published potency and affinity data on endogenous estrogens and their circulating concentrations in humans. At the molecular level, we used established molecular docking techniques to evaluate the potential for D4 and related chemicals to fit within and to activate or block the binding pocket of ERα. Our analyses indicate that the estrogenic effect of D4 is molecularly, biochemically, and physiologically implausible, which corroborates previous evaluations of D4 that concluded it is not an estrogenic endocrine disruptor. The claim that D4 exhibits estrogenic endocrine disruptive properties based on a presumed link between the results of screening-level assays (RUA and ERTA) and adverse effects is not supported by the data and relies on deficient evaluative and interpretative methods. Instead, a plausible mechanistic explanation for the various adverse effects of D4 observed in rodent studies, including its effects in reproduction studies, is that these are secondary to high-dose-dependent, physico-chemical effects that perturb cell membrane function and produce rodent-specific sensory irritation.

八甲基环四硅氧烷(D4)缺乏通过雌激素途径扰乱内分泌的潜力。
八甲基环四硅氧烷(D4)是一种挥发性高亲脂性单体,用于生产许多消费品中发现的有机硅聚合物,并广泛用于工业应用和工艺。许多关于D4毒理学的综述得出结论,D4对内分泌敏感终点的不良影响是通过依赖于全身毒性的MoA而不是通过内分泌活性介导的MoA发生的,但也有研究认为D4是一种雌激素内分泌干扰化学物质(EDC),基于筛选水平的实验结果表明D4与ERα相互作用,并且在高剂量时影响啮齿动物的雌激素敏感终点。为了解决这些不同的解释,我们在生物组织的生化和分子水平上测试了与D4与雌激素受体α亚型(ERα)相互作用有关的两个特定假设,以及在生理水平上与雌激素和抗雌激素途径有关的第三个特定假设。在生理水平上,我们采用既定的WoE方法,通过检查D4在啮齿动物毒理学研究中对er α相关终点的影响,来评估D4雌激素激动剂和拮抗剂活性的所有相关数据。在生化水平上,我们利用药理学中建立的方程计算了D4是否会对17β-雌二醇(E2)占用ERα产生显著的功能变化。为了进行这些计算,我们使用了大鼠研究中D4的效力和动力学数据,以及已发表的内源性雌激素的效力和亲和力数据及其在人体内的循环浓度。在分子水平上,我们使用已建立的分子对接技术来评估D4和相关化学物质的潜力,以适应并激活或阻断ERα的结合袋。我们的分析表明,D4的雌激素效应在分子、生物化学和生理学上都是不可信的,这证实了之前对D4的评价,即D4不是雌激素内分泌干扰物。基于筛选水平测定结果(RUA和ERTA)与不良反应之间的假定联系,D4表现出雌激素内分泌干扰特性的说法没有得到数据的支持,并且依赖于缺乏评估和解释方法。相反,对于D4在啮齿动物研究中观察到的各种不良影响,包括其在生殖研究中的影响,一个合理的机制解释是,这些不良影响是继发于高剂量依赖的物理化学效应,这些效应会扰乱细胞膜功能并产生啮齿动物特异性的感觉刺激。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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