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

Kalindi D. Hettiarachchi, Paul Zimmet, Nika N. Danial, Mark A. Myers

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

LanguageEnglish
Pages295-306
Number of pages12
JournalExperimental and Toxicologic Pathology
Volume60
Issue number4-5
DOIs
Publication statusPublished - 5 Aug 2008

Keywords

  • Apoptosis
  • Bafilomycin
  • Islet β cell
  • Type 1 diabetes
  • Vacuolar proton-translocating ATPase

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Toxicology
  • Cell Biology

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