Lifecourse sex-specific molecular response to early-life exposures of toxic substances

Toxicants in the environment can significantly impact physiology. Environmental chemical exposures during early developmental stages disturb normal embryonic development and programming, and dramatically impact long-term health as individuals age. Female and male animals show distinct phenotypes when responding to a given chemical exposure. Here, through the TaRGET II (Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription) consortium, we systematically explored sex-specific transcriptomic and epigenomic alterations in response to various toxicants, including arsenic (As), lead (Pb), tributyltin (TBT), bisphenol A (BPA), di(2-ethylhexyl) phthalate (DEHP), dioxin (TCDD), and fine particulate matter (PM2.5), across three time points in mice exposed two weeks prior to conception through gestation and lactation. After being exposed to toxicants during the embryonic and early postnatal developmental stages, 1,025 omics datasets were generated from the liver and analyzed across three mouse life stages. We discovered a significant sex-biased molecular response to distinct exposures in the liver at both the transcriptomic and epigenetic levels, showing dynamic changes across mouse development and aging. The perturbed pathways and transcription factors in response to different chemical exposures in both sexes were further evaluated to measure the sex-specific impact of each toxic exposure in the liver. Overall, this study presents the most detailed investigation of sex-specific molecular signatures under the influence of developmental exposures to toxic substances.