Transplacental exposure to the vacuolar-ATPase inhibitor bafilomycin disrupts survival signaling in β cells and delays neonatal remodeling of the endocrine pancreas

Abstract

A wave of β cell apoptosis occurs around 2 weeks of age in rats and mice. We have previously reported that exposure in utero to bafilomycin, a plecomacrolide antibiotic that inhibits the vacuolar (v)ATPase enzyme and contaminates the human diet, delays this neonatal wave and accelerates diabetes in non-obese diabetic (NOD) mice. Here we exposed C57BL/6J mice in utero to bafilomycin and assessed the effects on islet morphology, apoptosis and activation of cell survival signaling in β cells. The neonatal wave of β cell apoptosis was associated with high expression and low phosphorylation of the pro-apoptotic Bcl-2 family protein Bad, whereas after weaning (3 weeks of age) Bad was down-regulated and β cell apoptosis was low. In contrast, in bafilomycin-exposed mice the frequency of apoptotic β cells and the expression of Bad remained high after weaning. Bafilomycin exposure also inactivated the insulin/IGF signaling pathway intermediate, FoxO1, and increased the insulin content in neonatal islets. Thus, exposure in utero to bafilomycin disrupts the regulation of Bad in neonatal β cells, increases cell survival signaling and delays the neonatal wave of apoptosis. Increased expression of Bad in adult β cells provides an explanation for accelerated diabetes in bafilomycin-exposed NOD mice, whereby disruption of neonatal islet-cell turnover may render the adult β cells more susceptible to induced cell death.