It is increasingly evident that in-utero exposure to environmental chemicals (ECs), including endocrine disrupting compounds (EDCs), disturbs reproductive development in wildlife, domestic species and humans. Current thinking is that exposure to ECs is part of the mechanism driving increasing incidences of reproductive dysfunction in males and females, the latter characterised by statistics such as the 2% annual increase in EU breast cancer rates. Studies on a wide range of ECs, including phthalates, PCBs and dioxins, suggest the female reproductive tract is sensitive to chemical perturbation. However, many studies have focused on single or small numbers of ECs, on short-lived rodent species, and on high doses. These exposure modalities bear no relationship with normal human exposure.
We will use two complementary animal models in this proposal. The sheep, exposed to sewage sludge treated pastures, provides an established model of real-life exposure to a broad range of ECs at low/environmental concentrations. This long-lived mono-ovulatory species, with a pattern of gestational development similar to humans, is also part of the human food chain. The mouse is a more suitable model for more detailed mechanistic, epigenetic processes and transgenerational studies and, therefore, in combination with the sheep provides a powerful means of determining the impact of ECs in female reproductive development. We already know that di-2-ethylhexylphthalate and two polychlorinated biphenyl congeners preferentially accumulate in the ovine foetus following exposure of dams to sewage sludge treated pastures. Consequently, we propose to investigate the impact of these chemicals in vivo on the foetal sheep and mouse ovary, extending our observations to the pre-implantation embryo and F2 developing ovary.
We will utilise cutting-edge methodologies including transcriptomics, epigenomics, proteomics, and foetal ovary explant cultures. EC-sensitive genes and proteins identified in the animal models will direct investigations that utilise normal second trimester human foetal ovaries, thus providing a unique opportunity to establish the risks of ECs on human female reproductive development.
