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

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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.

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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).

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  1. Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA

    Joella Xu & Tai L. Guo

  2. Department of Environmental Health Sciences, University of Georgia, Athens, GA, 30602, USA

    Guannan Huang

  3. Department of Pathology, University of Georgia, Athens, GA, 30602, USA

    Tamas Nagy

  4. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, 30602, USA

    Quincy Teng

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  1. Joella Xu
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Correspondence to Tai L. Guo.

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Xu, J., Huang, G., Nagy, T. et al. Sex-dependent effects of bisphenol A on type 1 diabetes development in non-obese diabetic (NOD) mice. Arch Toxicol 93, 997–1008 (2019). https://doi.org/10.1007/s00204-018-2379-5

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