Transplacental exposure to the vacuolar-ATPase inhibitor bafilomycin disrupts survival signaling in beta cells and delays neonatal remodeling of the endocrine pancreas.
A wave of beta 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 beta cells. The neonatal wave of beta 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 beta cell apoptosis was low. In contrast, in bafilomycin-exposed mice the frequency of apoptotic beta 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 beta cells, increases cell survival signaling and delays the neonatal wave of apoptosis. Increased expression of Bad in adult beta cells provides an explanation for accelerated diabetes in bafilomycin-exposed NOD mice, whereby disruption of neonatal islet-cell turnover may render the adult beta cells more susceptible to induced cell death.
Hettiarachchi
Kalindi D
KD
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia.
Zimmet
Paul Z
PZ
Danial
Nika N
NN
Myers
Mark A
MA
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D018942:Macrolides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000096:biosynthesis / Q000187:drug effects
C494820:Bad protein, mouse; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D018942:Macrolides; D051025:bcl-Associated Death Protein; C052501:bafilomycin B1