New insights into the effect of bisphenol AF exposure on maternal mammary glands at various stages of gestation in mice

Bisphenol AF (BPAF) is the most estrogenic compound among BPA analogs. Mammary glands (MDs) are special organs that undergo repeated cycles of structural development, metabolism, and functional differentiation. Gestation is a sensitive window for MDs. In the present study, plug-positive CD-1 mice were exposed to vehicle (Veh) or 300 μg/kg BPAF through oral gavage every second day during gestation, and maternal MDs were collected from different developmental windows at 9.5, 13.5, and 18.5 d of gestation (gestation day [GD]9.5, GD13.5 and GD18.5). The results showed that gestational BPAF exposure induced a significantly elevated MD density at GD18.5. Non-target metabolomics analysis was used to screen for tyrosine, valine, ornithine, proline, threonine, phenylalanine and asymmetrical dimethylarginine (ADMA) amino acids, which changed significantly at all time points. Furthermore, the mRNA expression levels of genes related to these amino acids also changed significantly. Additionally, amino acid levels in BPAF-treated MGs at GD18.5 were related to the serum ammonia concentration of the corresponding offspring. These results provide a comprehensive view of the adverse effects of BPAF exposure during gestation on the maternal MG structure and function, which may affect milk components during lactation. Moreover, higher amino acids content may lead to amino acid imbalance or hyperammonemia in newborns.