Transgenerational consequences of pre-conceptional and in utero exposure to real-life chemical mixtures on fertility and metabolic health

摘要 人类健康面临的全球性挑战包括有据可查的人类生育率下降和急剧增加 肥胖相关代谢紊乱的患病率。现在有令人信服的证据表明，这些健康 挑战与可能影响内分泌活动的环境化学品有关。但这 前提是从对遗传受限的动物急性单一化学品暴露的研究中发展而来的 模型拟议的研究将解决中心假设，即暴露于现实生活中的混合物， 环境化学品，在怀孕之前和整个怀孕期间，导致跨代表观遗传效应， 影响新陈代谢和繁殖后代。该提案将使用一种独特的，现实生活中的化学品暴露 以及绵羊暴露于生物固体的预防相关动物模型。人类暴露在 环境化学品的广泛混合物，通常浓度较低，贯穿其使用寿命。放牧 一只怀孕的绵羊在用人类污水产生的生物固体处理的牧场上提供了一个早熟的模型。 有着和人类相似的发展轨迹。这提供了一种新的方法来检查的影响， 我们都接触到的环境化学混合物。其具体目标是：（1）缩短寿命 跨越三代（即F1、F2和F3）的雄性和雌性后代的代谢功能变化 在F0暴露于生物固体处理的牧场后;（2）评估雄性和 F0暴露于生物固体牧场后三代（即F1、F2和F3）的雌性后代;（3） 确定表观遗传变化及其与转录网络的功能关系， 母体生物固体暴露对后代代谢和生育力的跨代影响。这 全面的分析将提供关于现实生活中化学品暴露影响的概念验证数据， 相关的实验范式。这将大大增强我们预测和告知政策的能力 发展的目的是改善环境化学品接触的有害影响， 代谢和生殖健康。

Abstract Global challenges to human health include a well-documented decline in human fertility and a dramatic increase in the prevalence of obesity related metabolic disorders. There is now compelling evidence that these health challenges are associated with environmental chemicals that can influence endocrine activity. However, this premise has evolved from studies with acute single chemical exposures in altricial, genetically restricted, animal models. The proposed study will address the central hypothesis that exposure to a real-life mixture of environmental chemicals, prior to and throughout pregnancy, results in transgenerational epigenetic effects in offspring that affect metabolism and reproduction. The proposal will use a unique, real-life chemical exposure and a translationally relevant animal model whereby sheep are exposed to biosolids. Humans are exposed to a wide mixture of environmental chemicals, at typically low concentrations, throughout their lifespan. Grazing pregnant sheep on pastures treated with biosolids generated from human sewage provides a precocial model with a developmental trajectory similar to humans. This provides a novel approach to examine the effects of environmental chemical mixtures to which we are all exposed. The specific aims are: (1) to characterise lifetime changes in metabolic function of male and female offspring spanning three generations (i.e. F1, F2 and F3) following F0 exposure to biosolids treated pasture; (2) to assess changes in reproductive potential of male and female offspring across three generations (i.e. F1, F2 and F3) following F0 exposure to biosolids pasture; (3) to determine epigenetic changes, and their functional relationships, to transcriptional networks governing transgenerational effects of maternal biosolids exposure on offspring metabolism and fertility. This comprehensive analysis will provide proof-of-concept data on the effects of real-life chemical exposure in a relevant experimental paradigm. This will significantly enhance our ability to predict and inform policy development with the aim of ameliorating detrimental effects of environmental-chemical exposure and to improve metabolic and reproductive health.