Center for Occupational and Environmental Health, University of California, Irvine, Irvine, California, USA.
School of Public Health, University of California, Berkeley, Berkeley, California, USA.
Environ Health Perspect. 2019 Jul;127(7):75001. doi: 10.1289/EHP4971. Epub 2019 Jul 19.
Identification of female reproductive toxicants is currently based largely on integrated epidemiological and toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking.
We sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification.
A working group of international experts was convened to discuss mechanisms associated with chemical-induced female reproductive toxicity and identified 10 key characteristics of chemicals that cause female reproductive toxicity: 1) alters hormone receptor signaling; alters reproductive hormone production, secretion, or metabolism; 2) chemical or metabolite is genotoxic; 3) induces epigenetic alterations; 4) causes mitochondrial dysfunction; 5) induces oxidative stress; 6) alters immune function; 7) alters cell signal transduction; 8) alters direct cell–cell interactions; 9) alters survival, proliferation, cell death, or metabolic pathways; and 10) alters microtubules and associated structures. As proof of principle, cyclophosphamide and diethylstilbestrol (DES), for which both human and animal studies have demonstrated female reproductive toxicity, display at least 5 and 3 key characteristics, respectively. 2,3,7,8-Tetrachlorodibenzo--dioxin (TCDD), for which the epidemiological evidence is mixed, exhibits 5 key characteristics.
Future efforts should focus on evaluating the proposed key characteristics against additional known and suspected female reproductive toxicants. Chemicals that exhibit one or more of the key characteristics could be prioritized for additional evaluation and testing. A key characteristics approach has the potential to integrate with pathway-based toxicity testing to improve prediction of female reproductive toxicity in chemicals and potentially prevent some toxicants from entering common use. https://doi.org/10.1289/EHP4971.
目前，女性生殖毒性剂的鉴定主要基于综合的流行病学和毒理学数据，在较小程度上也基于机制数据。缺乏一种系统地搜索、组织、整合和评估来自各种数据类型的女性生殖毒性机制证据的统一方法。
我们试图应用类似于致癌危害识别中首创的关键特征方法来识别女性生殖毒性剂的危害。
召集了一个国际专家工作组，讨论与化学物质引起的女性生殖毒性相关的机制，并确定了导致女性生殖毒性的 10 种化学物质的关键特征：1）改变激素受体信号；改变生殖激素的产生、分泌或代谢；2）化学物质或代谢物具有遗传毒性；3）诱导表观遗传改变；4）引起线粒体功能障碍；5）诱导氧化应激；6）改变免疫功能；7）改变细胞信号转导；8）改变直接的细胞-细胞相互作用；9）改变存活、增殖、细胞死亡或代谢途径；10）改变微管和相关结构。作为原理证明，环磷酰胺和己烯雌酚（DES），这两种物质都有人类和动物研究表明具有女性生殖毒性，分别显示至少 5 和 3 个关键特征。2,3,7,8-四氯二苯并对二恶英（TCDD），其流行病学证据参差不齐，表现出 5 个关键特征。
未来的工作应集中于针对其他已知和疑似的女性生殖毒性剂评估提出的关键特征。表现出一个或多个关键特征的化学物质可以优先进行进一步评估和测试。关键特征方法有可能与基于途径的毒性测试相结合，以提高对化学物质的女性生殖毒性的预测，并可能防止一些毒性剂进入常规使用。https://doi.org/10.1289/EHP4971.
