Bisphenol A and bisphenol S disruptions of the mouse placenta and potential effects on the placenta–brain axis

Abstract

Placental trophoblast cells are potentially at risk from circulating endocrine-disrupting chemicals, such as bisphenol A (BPA). To understand how BPA and the reputedly more inert bisphenol S (BPS) affect the placenta, C57BL6J mouse dams were fed 200 μg/kg body weight BPA or BPS daily for 2 wk and then bred. They continued to receive these chemicals until embryonic day 12.5, whereupon placental samples were collected and compared with unexposed controls. BPA and BPS altered the expression of an identical set of 13 genes. Both exposures led to a decrease in the area occupied by spongiotrophoblast relative to trophoblast giant cells (GCs) within the junctional zone, markedly reduced placental serotonin (5-HT) concentrations, and lowered 5-HT GC immunoreactivity. Concentrations of dopamine and 5-hydroxyindoleacetic acid, the main metabolite of serotonin, were increased. GC dopamine immunoreactivity was increased in BPA- and BPS-exposed placentas. A strong positive correlation between 5-HT+GCs and reductions in spongiotrophoblast to GC area suggests that this neurotransmitter is essential for maintaining cells within the junctional zone. In contrast, a negative correlation existed between dopamine+GCs and reductions in spongiotrophoblast to GC area ratio. These outcomes lead to the following conclusions. First, BPS exposure causes almost identical placental effects as BPA. Second, a major target of BPA/BPS is either spongiotrophoblast or GCs within the junctional zone. Third, imbalances in neurotransmitter-positive GCs and an observed decrease in docosahexaenoic acid and estradiol, also occurring in response to BPA/BPS exposure, likely affect the placental–brain axis of the developing mouse fetus.

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

“…Additionally, during organogenesis and tissue repair different cell types with different receptors interact to form organs, increasing the complexity of interactions and thus the likelihood of non-monotonic dose-response curves [231]. But, perhaps more importantly, we applied a rigorous mixOmics approach [21], as done in previous BPA studies performed in the Rosenfeld Laboratory [22][23][24], to ascertain whether the low dose of BPA simultaneously affected several endpoints in different laboratories. As such, if low-dose effects in the same animals are identified across multiple systems, it seems unlikely that these findings are not important.…”

“…To achieve these lofty goals, we used the mixOmics R package [21], as we have done in previous BPA studies performed in the Rosenfeld Laboratory [22][23][24]. In this case, we used the program to correlate data obtained by independent CLARITY-BPA investigators.…”

“…In this integrative correlation analyses section, we emphasize first those associations identified in males and females at the lowest dose and at 6 months of age, as evidence of such persistent or developmental origins of health and disease (DOHaD) effects would suggest that we need to rethink the lowest safe dose of BPA. Rosenfeld's laboratory has used this mixOmics analyses approach in previous BPA studies to integrate various 'omics and phenotypic data generated in her lab together [22][23][24]. However, to our knowledge, this is the first time such a program has been used to perform integrative correlation analyses with comprehensive datasets spanning different ages and dosages and generated in the laboratories of multiple investigators.…”

Changes in nucleus accumbens gene expression accompany sex-specific suppression of spontaneous physical activity in aromatase knockout mice

“…To examine for potential associations between those genes that were identified by false discovery rate (FDR) to be differentially expressed and phenotypic changes, Pearson correlations were performed, as we have done previously (Manshack et al, 2017;Mao et al, 2020). This was done two ways: 1) values were calculated across all mice and 2) only based on female results, as these were the most pronounced.…”

The placenta‐brain‐axis

“…One study, however, suggests that the placenta relies on transport of maternal 5‐HT (Kliman et al, 2018). In our recently published studies, we found that exposure to endocrine‐disrupting chemicals (EDC), bisphenol A (BPA) and bisphenol S (BPS) lower the total concentrations of 5‐HT in the placenta (Mao et al, 2020). Additionally, we localized 5‐HT to trophoblast giant cells, which are in contact with the underlying uterine tissue, but the number of giant cells staining immunopositive for 5‐HT was reduced with BPA or BPS exposure (Mao et al, 2020).…”