Developmental low-dose bisphenol A exposure leads to extensive transcriptome female masculinization and male feminization later in life

BACKGROUND: Bisphenol A (BPA) is an endocrine disruptor, and exposure to low doses in utero has been associated with the development of metabolic diseases. Previous studies have suggested that bone marrow (BM) may be particularly susceptible to BPA exposure. METHODS: Here, we investigate how developmental exposure to low levels of BPA affects the BM transcriptome and the blood metabolic profile in Fischer 344 rats later in life. We compare these effects to those observed in human metabolic syndrome (MetS) using a population-based cohort. RESULTS: The results show an unexpectedly extensive sex-biased effect on the BM transcriptome from a BPA dose approximately eight times lower than the recent temporary European Food Safety Authority (EFSA) human tolerable daily intake (TDI) and a higher dose considered safe in 2015. BPA exposure induces sex-specific changes in gene expression, progressing toward a hypometabolic cancer-like state in females and a hypermetabolic autoimmunity-like state in males, with a blood metabolic profile that significantly overlaps with human MetS in a cross-sectional study. CONCLUSIONS: We conclude that developmental low-dose BPA exposure might induce metabolic syndrome specifically in males, possibly by affecting T cell activity in a sex-specific manner. Our study provides biologically plausible and convincing evidence for significant effects from low-dose BPA exposure, supporting the substantial lowering of the human BPA TDI by EFSA based on its critical effects on T cells.