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Sex-dependent effects of bisphenol A on type 1 diabetes development in non-obese diabetic (NOD) mice

  • Joella Xu
  • Guannan Huang
  • Tamas Nagy
  • Quincy Teng
  • Tai L. GuoEmail author
Organ Toxicity and Mechanisms

Abstract

Type 1 diabetes (T1D) is an autoimmune disease caused by immune-mediated pancreatic β-cell destruction. The endocrine disrupting chemical bisphenol A (BPA) has widespread human exposure and can modulate immune function and the gut microbiome (GMB), which may contribute to the increasing T1D incidence worldwide. It was hypothesized that BPA had sex-dependent effects on T1D by modulating immune homeostasis and GMB. Adult female and male non-obese diabetic (NOD) mice were orally administered BPA at environmentally relevant doses (30 or 300 µg/kg). Antibiotic-treated adult NOD females were exposed to 0 or 30 µg/kg BPA. BPA accelerated T1D development in females, but delayed males from T1D. Consistently, females had a shift towards pro-inflammation (e.g., increased macrophages and Bacteroidetes), while males had increases in anti-inflammatory immune factors and a decrease in both anti- and pro-inflammatory GMB. Although bacteria altered during sub-acute BPA exposure differed from bacteria altered from chronic BPA exposure in both sexes, the GMB profile was consistently pro-inflammatory in females, while males had a general decrease of both anti- and pro-inflammatory gut microbes. However, treatment of females with the antibiotic vancomycin failed to prevent BPA-induced glucose intolerance, suggesting changes in Gram-positive bacteria were not a primary mechanism. In conclusion, BPA exposure was found to have sex dimorphic effects on T1D with detrimental effects in females, and immunomodulation was identified as the primary mechanism.

Keywords

Bisphenol A Type 1 diabetes NOD mice Immunomodulation Microbiome Vancomycin 

Notes

Acknowledgements

The authors would like to thank Daniel E. Lefever, Dr. Travis Glenn and his lab members, and the Georgia Genomics and Bioinformatics Core of UGA for their help with the 16S rRNA library preparation, sequencing and bioinformatics analysis, and CVM Cytometry Core Facility (the College of Veterinary Medicine, UGA) for assisting flow cytometric analysis. This study was supported by NIH R21ES24487, and in part by NIH R41AT009523 and Interdisciplinary Toxicology Program at University of Georgia (UGA).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

204_2018_2379_MOESM1_ESM.pdf (992 kb)
Supplementary material 1 (PDF 991 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary MedicineUniversity of GeorgiaAthensUSA
  2. 2.Department of Environmental Health SciencesUniversity of GeorgiaAthensUSA
  3. 3.Department of PathologyUniversity of GeorgiaAthensUSA
  4. 4.Department of Pharmaceutical and Biomedical Sciences, College of PharmacyUniversity of GeorgiaAthensUSA

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