基于孕前出生队列研究三氯生暴露对女性生殖健康的影响、机制探讨及营养干预

Triclosan (TCS), a common antimicrobial agent in personal care products, has been recognized as a new environmental endocrine disruptor (EED). Some overseas countries have initiated restriction on TCS application while little attention has been raised in China. Women of childbearing age or in pregnancy are particularly vulnerable to EEDs. Based on an ‘EEDs exposure and infertility’ case-control study and a small cohort study, we observed the most significant effect of TCS on women’s reproductive function among a list of common EEDs, which raises an urgent need to explore the effects and mechanisms in prospective birth cohorts with large sample sizes.We will recruit more couples planning for pregnancy based on our established preconception birth cohort. Urinary TCS exposure levels will be timely quantified and women’s menstruation, time to pregnancy as well as infants’ birth outcomes, anogenital distance, growth and development, etc. will be followed up in different reproductive stages. Besides, based on the exposure levels of the study population, we plan to explore the reproductive endocrine disrupting effects and mechanisms of chronic low dose exposure to TCS in animal studies by focusing on the ovarian steroidogenesis. Corresponding in vitro studies will be conducted to verify the findings and to look for potential targets. Moreover, along with the cohort study as well as the in vivo and in vitro studies, we will test the possibility of Vitamin D, which has been found with potential in female reproductive regulation, as an antagonism to the reproductive toxicity of TCS and the potential mode of action. The present study will provide a scientific basis for government decision-making on the safety limit of TCS, nutritional interventions as well as protections of vulnerable population.

三氯生（TCS）在个人护理品中广泛应用，属于新型环境内分泌干扰物（EEDs），国外已强烈建议勿用此类产品，而我国尚未引起重视。育龄及孕期女性对EED尤为敏感，我们前期“EEDs与不孕”的病例-对照及小样本队列研究发现，在众多常见EEDs中，TCS明显影响育龄妇女的生殖功能，亟待通过大样本前瞻性队列深入研究。本项目将依托已建立孕前出生队列，扩大招募备孕夫妇，于不同生殖阶段定量测定TCS暴露水平，并随访月经、备孕时间、出生结局、新生儿肛殖距和生长发育等情况。同时，以人群的实际暴露水平设置染毒剂量，从卵巢性激素合成通路改变角度，以动物实验研究低剂量TCS慢性暴露的生殖功能损害及关键作用途径；体外实验进一步验证并寻找关键作用靶点。此外，结合人群和体内外实验，探讨具有调控女性生殖潜能的维生素D是否可拮抗TCS的生殖毒性及可能机制。本项目将为我国制定TCS安全限值、营养干预和保护易感人群提供重要依据。

三氯生（TCS）在个人护理品中广泛应用，属于新型环境内分泌干扰物（EEDs），国外已强烈建议勿用此类产品，而我国尚未引起重视。育龄及孕期女性对EED尤为敏感，TCS是否影响育龄妇女的生殖功能，亟待通过大样本前瞻性队列深入研究。本项目依托已建立大型出生队列，评估了上海地区育龄妇女孕前及孕期TCS暴露水平，发现孕妇尿液中TCS普遍检出但水平较低（孕早期TCS中位浓度为0.54μg/L；孕中期为0.32μg/L）。进一步随访妇女月经特征、备孕时间、不孕以及脐血性激素、新生儿肛殖距、出生结局等情况，发现育龄妇女TCS暴露可能对不孕和月经周期产生一定影响，但对备孕时间及其他月经特征无显著影响；此外，孕早期TCS暴露与男婴肛殖距呈负相关，但未发现孕期TCS暴露与脐血性激素及出生结局指标之间有显著相关性。同时，通过人群研究，探讨具有调控女性生殖潜能的维生素D是否可拮抗TCS的生殖毒性，结果发现维生素D缺乏，会增加TCS引起的女性不孕的风险，但未发现维生素D水平在TCS暴露与新生儿肛殖距及出生结局关系中的作用。体内外机制研究发现，TCS通过影响下丘脑-垂体-性腺轴，破坏雌激素代谢，进而影响了雌性生殖发育，GnRH(cAMP/PKA)可能是其关键作用通路。本研究结果提示目前上海孕妇处于较低水平的TCS暴露，未观察到TCS暴露对女性生殖及子代健康产生显著影响，但考虑到其与不孕及新生儿肛殖距有关，并且育龄及孕期女性属于易感人群，TCS暴露对女性生殖及子代健康的影响值得进一步关注。