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

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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.