Maternal Bisphenol B Exposure and Mammary Gland Development of Offspring: A Time-Series Analysis

Abstract

Breast cancer incidence has increased and become the world's most prevalent cancer, which is related to abnormal development of mammary glands and thought to be influenced by environment endocrine disruptors such as bisphenol A (BPA). However, whether its substitution, bisphenol B (BPB), has similar effects remains a concern. In the present study, a maternal exposure model of ICR mice combined time-series RNA-seq analysis was established to explore the underlying correlation among maternal BPB exposure (300 μg/kg body weight), mammary gland development, and longterm breast health in offspring. The results showed that BPB exposure disrupted hormonal homeostasis of the female offspring but did not affect the branch development of mammary glands in a time-dependent manner. However, at postnatal day 90 (PND90), BPB exposure resulted in duct dilatation, lobular hyperplasia, and inflammatory cell infiltration and increased the number of hormone receptor-expressing (HR + ) luminal cells in offspring. Further, the differentially expressed genes in timeseries analysis of RNA-seq for mammary glands of the female offspring were enriched in the morphogenesis of branching structures, branching epithelium, and branching morphogenesis of epithelial tubes, which are always considered gland development. Interestingly, the results of RNA-seq also suggested that progesterone receptor (Pgr) mRNA expression in the BPB group was elevated at PND90, and breast cancer related genes such as GATA binding protein 3 (Gata3) and epidermal growth factor receptor (Egfr) were also altered. These findings suggested that maternal BPB exposure did not accelerate mammary gland development or lead to obvious morphological anomalies of offspring, but it induced pathological changes and altered cancer related gene expression in adult offspring breast.

Invisible Hand behind Female Reproductive Disorders: Bisphenols, Recent Evidence and Future Perspectives

“…Administration of BPA/BPS to animals during pregnancy may lead to an increase in the proportion of dopamine+ trophoblast giant cells (GCs), while the proportion of serotonin+ GCs correspondingly decreases, which may affect the placental–brain axis of the developing fetus [ 22 ]. Exposure to BPB and BPAF leads to accelerated differentiation of the mammary glands (MGs), and in addition, non-targeted metabolomics results show significantly elevated amino acid levels within the maternal MGs, which can lead to an amino acid imbalance or hyperammonemia in newborns [ 23 , 24 ]. The imbalance of placental and breast functions leads to abnormal fetal development and altered expression of genes related to carcinogenesis in the adult offspring.…”