Sex- and dose-specific effects of maternal bisphenol A exposure on pancreatic islets of first- and second-generation adult mice offspring

Amita Bansal, Cetewayo Rashid, Frances Xin, Changhong Li, Erzsebet Polyak, Anna Duemler, Tom van der Meer, Martha Stefaniak, Sana Wajid, Nicolai Doliba, Marisa S. Bartolomei, Rebecca A. Simmons

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

BACKGROUND: Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring. OBJECTIVE: We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets. METHODS: Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10 μg/kg/d-LowerB and 10 mg/kg/d-UpperB). RESULTS: Both doses of BPA significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and UpperB induced islet inflammation in male F1 offspring that persisted into the next generation. We also observed dose-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced β-cell mass and increased β-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important β-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation. CONCLUSION: These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications.

Original languageEnglish
Article number097022
JournalEnvironmental Health Perspectives
Volume125
Issue number9
DOIs
StatePublished - Sep 2017

Bibliographical note

Funding Information:
This work is supported by the National Institute of Environmental Health Sciences/National Institutes of Health (ES023284 and ES013508 [M.S.B., R.A.S.]); March of Dimes (M.S.B.); the Perelman School of Medicine Center of Excellence in Environmental Toxicology (CEET-ES-013508-05 [R.A.S.], RO1DK098517 [C.L.], and T32 ES019851 [F.X.]), the Bioenergetics Core of the Children’s Hospital of Philadelphia and Development Disabilities Research Center (IDDRC; U54-HD086984), and the Islet Cell Biology Core of the Penn Diabetes Institute for Diabetes, Obesity & Metabolism (P30DK19525).

Funding Information:
The authors would like to acknowledge D. Condon, Z. (Paul) Wang, T. Kim, and M. Li for their bioinformatics and biostatistics input. We are also grateful for the services of the University of Pennsylvania Next Generation Sequencing Core and the Radioimmunoassay and Biomarkers Core (P30 DK19525), and the Children’s Hospital of Philadelphia Pathology Core. This work is supported by the National Institute of Environmental Health Sciences/National Institutes of Health (ES023284 and ES013508 [M.S.B., R.A.S.]); March of Dimes (M.S.B.); the Perelman School of Medicine Center of Excellence in Environmental Toxicology (CEET-ES-013508-05 [R.A.S.], RO1DK098517 [C.L.], and T32 ES019851 [F.X.]), the Bioenergetics Core of the Children’s Hospital of Philadelphia and Development Disabilities Research Center (IDDRC; U54-HD086984), and the Islet Cell Biology Core of the Penn Diabetes Institute for Diabetes, Obesity & Metabolism (P30DK19525).

Publisher Copyright:
© 2017, Public Health Services, US Dept of Health and Human Services. All rights reserved.

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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