产前全氟辛烷磺酸（PFOS）暴露对雄性子代生殖功能的影响

The 2013 report by United Nations Environment Programme (UNEP)/World Health Organization (WHO) indicated that the prevalence of human reproductive disorders is growing. Another WHO report indicated that 1 in every 4 couples in developing countries had been found to be affected by infertility, posing heavy financial burden to the health care system globally. In recent years, large of amount of literature has established a positive correlation between exposure of environmental pollutants and the increased risk of male sub-fecundity on wildlife and humans. In particular, endocrine-disrupting chemicals (EDCs) have been identified as one of the global concerns. Current hypothesis suggests that EDCs interfere with androgen and/or estrogen receptors, affecting reproductive health of wildlife and humans. However the proposed underlying mechanistic actions are not yet conclusive. .Among the EDC’s, of special interest are the emerging global pollutants perfluoroalkyl acids (PFAAs) and the notorious family member perfluorooctane sulfonate (PFOS). They are non-biodegradable, leading to their wide presence in the environment and a very lengthy serum elimination half-life in animals. .PFOS is ubiquitous in the environment. It is commonly absorbed orally and has the ability to cross the placenta, increasing susceptibility of exposure to the fetus. Epidemiological studies have associated maternal blood plasma levels of PFAAs to sub-fecundity, fewer counts of normal sperm and infertility. Laboratory animal studies revealed that adult exposure to PFOS reduced synthesis of male sex hormone and the production of sperm. However the underlying molecular mechanisms, from exposure to generating the effects on testicular functions, especially at the early fetal development stage are still unknown. .This proposal uses a prenatal animal exposure model, combining with molecular, lipidomics and physiological approaches to obtain multiple lines of evidence to decipher the perturbing effects of PFOS on the cytochrome P450-arachidonate cascade, which leads to the production of lipid-signaling mediators, ultimately affecting normal fetal testis development. The consequential testicular phenotypes and functions will be examined in the adult offspring. The identification of the molecular targets and the associated lipidomics changes in PFOS-elicited reproductive dysfunction would deepen our understanding on the non-genetic causes of reproductive diseases. This will help to evaluate the risk of public exposure of PFOS and provide invaluable insights for clinicians and policy makers to develop sustainable, remedial strategies to this environmental and healthcare challenge, thus providing long term impact to the community for many generations to benefit.

当前，内分泌干扰物（EDCs）已被确定为全球最为关注的问题之一。新兴污染物全氟辛烷磺酸（PFOS）因其独特的生物特性尤其引人关注。目前认为，EDCs通过干扰机体雄激素和/或雌激素受体而影响机体的生殖健康，而其所涉及的具体分子机制还没有定论。流行病学表明，母体血浆PFOS与子代低繁殖力、精子数量减少及不孕有关。我们前期的实验发现，PFOS暴露的雄鼠导致雄性激素分泌紊乱和精子数量减少。然而，潜在的分子机制（尤其在整个发育阶段）还未被深入探讨。因此，本课题拟建立产前污染物暴露的动物模型，运用分子、脂质组学及生理病理学相结合的研究手段，旨在系统深入地探讨PFOS对调控脂质信号介质生成的细胞色素P450-花生四烯酸级联信号通路的干预作用，进而分析其对胎儿，新生和成年子代中相应的睾丸结构与功能表型的影响。由此，PFOS引起生殖功能障碍相关的分子网络调控机制和分子靶标的鉴定将有助于进一步了解生殖系统疾病

世界卫生组织与联合国环境规划署于2013年发布的报告中表明患有生殖障碍的个体比例在不断提高，生殖疾病对于人类的影响日益严峻。其中，流行病学结果表明，内分泌干扰物（EDCs）被认为可以通过干扰个体雄或雌激素受体进而影响生殖能力。全氟辛酸(PFOS)作为一种内分泌干扰物，我们前期的结果表明其能导致雄鼠激素分泌紊乱，精子数量下降。基于本项项目，我们发表了四篇文章关于环境污染与生殖相关文章，揭示了胚胎时期暴露于PFOS导致雄性新生小鼠的睾丸组织中脂质组和转录组表达模式改变，揭示了全氟辛酸在影响睾丸功能的脂质组和代谢组作用，揭示了睾丸支持细胞中动力蛋白1和肌球蛋白VIIa参与细胞骨架调节，维持正常生精作用。