Effects Of Bisphenol A (an Endocrine-disrupting Chemical) On Glucose Homeostasis And The Function Of Pancreatic Beta-cell In Mice

Part 1 Perinatal exposure to bisphenol A and glucose homeostasis: the critical window of exposureBisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100μg/kg/day) at different time of perinatal stage:1) on days 1-6 of pregnancy (P1-P6, preimplantation exposure); 2) from day 6 of pregnancy until postnatal day (PND) 0 (P6-PND0, fetal exposure); 3) from lactation until weaning (PND0-PND21, neonatal exposure); and 4) from day 6 of gestation until weaning (P6-PND21, fetal and neonatal exposure). At 3,6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and β-cell function were measured.The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of β-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than β-Cell mass, were consistent with the development of glucose intolerance.Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure.Part 2 Long-term effect of perinatal exposure to bisphenol A on adipose tissue mass and lipid metabolismBisphenol A, a widely used environmental endocrine disruptor, has been reported to disrupt metabolism homeostasis. BPA exposure is a risk factor for type 2 diabetes. But it is unclear whether BPA exposure caused the development of hyperlipidemia. The aim of this study was to investigate the long-term effect of perinatal exposure to BPA on adipose tissue mass and lipid metabolism in mothers and offspring. Pregnant mice were exposed to BPA by s.c.injection 100ug/kg/d at different time of perinatal stage. The adipose tissue weight and plasma lipid levels were measured in mothers and offspring at postnatal month 3 and 8. Morphology analysis of adipose tissue was done.At 3 months of age, plasma triglyceride and cholesterol levels increased significantly in P6-PND0, PND0-PND21 and P6-PND21 male offspring. While in female offspring, only the P6-PND0 mice showed the higher plasma lipid levels. BPA exposure during gestation and lactation had long-term consequences for mothers: 3 months postpartum, treated mice had higher plasma triglyceride and cholesterol levels than untreated females. The WAT mass was increased in BPA-treated mothers and offspring, and the increase of adipose tissue was associated with an increase in size of adipocytes (hypertrophy). At the age of 8 months, neither mothers nor offspring showed lipid metabolism dysfunction or morphology abnormalbility. The changes of lipid metabolism in BPA-treated mice were comparable of the changes of glucose tolerance.In conclusion, perinatal exposure to BPA had long-term consequences on lipid metabolism for both mothers and offspring. And this effect was sex and time-dependent.Part 3 Involvement of GPER in the impairment of glucose homeostasis induced by bisphenol A in adult miceE2 and its mimetics (BPA) have long been known to modulate pancreatic function by the estrogen receptors signaling pathways. The estrogen receptors-ERa, ERβ and GPER (G protein-coupled estrogen receptor) are espressed in islet β-cell. It is now accepted that ERa and ERβ can act respectively to initiate different signaling cascades that regulate the insulin biosynthesis and secretion functions of islet β-cell. But little is known regarding the role of GPER in activating signal transduction cascades in β-cells. The objective of the present study was to identify whether GPER involved in the impairment of glucose homeostasis induced by bisphenol A in adult mice.In vivo, G1、BPA and E2 all increased the insulin release and insulin content. In vitro, G1、BPA and E2 could increased the insulin secretion stimulated by 16.7mmol/L glucose. Meanwhile, they also increased the insulin content, and these effects were inhibited by G15. This suggested that GPER involved in the regulation of glucose homeostasis induced by bisphenol A in adult mice.