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

摘要 对人类健康的全球挑战包括有据可查的人类生育率下降和急剧增加 与肥胖相关的代谢紊乱的流行。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物质有关。不过，这个 Premise是从急性单一化学物质暴露的研究演变而来的，这些研究是在遗传受限的动物身上进行的 模特们。这项拟议的研究将解决中心假设，即接触到现实生活中的 环境化学品，在怀孕前和整个怀孕期间，导致跨代表观遗传效应 影响新陈代谢和生殖的后代。该提案将使用一种独特的、现实生活中的化学暴露 以及一种与翻译相关的动物模型，即绵羊接触生物固体。人类暴露在一种 广泛的环境化学品混合物，通常浓度较低，在其整个生命周期内。放牧 用人类污水产生的生物固体处理牧场上的怀孕绵羊提供了一个早熟模型 有着与人类相似的发育轨迹。这提供了一种新的方法来检验 我们都暴露在环境化学混合物中。具体目标是：(1)刻画终身 三代(F1、F2、F3)雌雄后代代谢功能的变化 在F0暴露于经过生物固体处理的牧草后；(2)评估雄性和 在F0暴露于生物固体牧场后，雌性后代跨越三代(即F1、F2和F3)； 确定表观遗传变化及其与转录网络的功能关系 母亲接触生物固体对后代新陈代谢和生育能力的跨代影响。这 综合分析将提供关于现实生活中化学品暴露的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，目的是改善环境化学品暴露的有害影响并改善 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.