Susceptibility to Low Vitamin B6 Diet-induced Gestational Diabetes Is Modulated by Strain Differences in Mice.

Gestational diabetes is a common pregnancy complication that adversely influences the health and survival of mother and child. Pancreatic islet serotonin signaling plays an important role in ß-cell proliferation in pregnancy, and environmental and genetic factors that disrupt serotonin signaling are associated with gestational diabetes in mice. Our previous studies show that pregnant C57BL/6J mice fed a diet that is low in vitamin B6, a critical co-factor in serotonin synthesis, develop hyperglycemia and glucose intolerance, phenotypes that are consistent with gestational diabetes in humans. The current study shows that, unlike in the C57BL/6J mice, low vitamin B6 diet does not alter glucose tolerance and insulin secretion in pregnant DBA/2J mice. The hypothesis to be tested in the current study is that pregnant DBA/2J mice are protected against low vitamin B6-induced gestational diabetes due to their higher expression and enzymatic activities of tissue nonspecific alkaline phosphatase (ALPL) relative to C57BL/6J. ALPL is a rate-limiting enzyme that regulates vitamin B6 bioavailability. Interestingly, treating pregnant DBA/2J mice with 7.5 mg/kg/day of the ALPL inhibitor SBI-425 is associated with glucose intolerance in low vitamin B6-fed mice, implying that inhibition of ALPL activity is sufficient to modulate resilience to low vitamin B6-induced metabolic impairment.

Evaluating the Effects of BPA and TBBPA Exposure on Pregnancy Loss and Maternal-Fetal Immune Cells in Mice.

BACKGROUND: Bisphenol A (BPA) exposure has been linked to miscarriages and pregnancy complications in humans. In contrast, the potential reproductive toxicity of BPA analogs, including tetrabromobisphenol A (TBBPA), is understudied. Furthermore, although environmental exposure has been linked to altered immune mediators, the effects of BPA and TBBPA on maternal-fetal immune tolerance during pregnancy have not been studied. The present study investigated whether exposure resulted in higher rates of pregnancy loss in mice, lower number of regulatory T cells (Tregs), and lower indoleamine 2,3 deoxygenase 1 (Ido1) expression, which provided evidence for mechanisms related to immune tolerance in pregnancy. OBJECTIVES: The purpose of this investigation was to characterize the effects of BPA and TBBPA exposure on pregnancy loss in mice and to study the percentage and number of Tregs and Ido1 expression and DNA methylation. METHODS: Analysis of fetal resorption and quantification of maternal and fetal immune cells by flow cytometry were performed in allogeneic and syngeneic pregnancies. Ido1 mRNA and protein expression, and DNA methylation in placentas from control and BPA- and TBBPA-exposed mice were analyzed using real-time quantitative polymerase chain reaction, immunofluorescence, and bisulfite sequencing analyses. RESULTS: BPA and TBBPA exposure resulted in higher rates of hemorrhaging in early allogeneic, but not syngeneic, conceptuses. In allogeneic pregnancies, BPA and TBBPA exposure was associated with higher fetal resorption rates and lower maternal Treg number. Importantly, these differences were associated with lower IDO1 protein expression in trophoblast giant cells and higher mean percentage Ido1 DNA methylation in embryonic day 9.5 placentas from BPA- and TBBPA-exposed mice. DISCUSSION: BPA- and TBBPA-induced pregnancy loss in mice was associated with perturbed IDO1-dependent maternal immune tolerance. https://doi.org/10.1289/EHP10640.