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

Arch Toxicol. 2019 Apr;93(4):997-1008. doi: 10.1007/s00204-018-2379-5. Epub 2019 Jan 2.


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; Immunomodulation; Microbiome; NOD mice; Type 1 diabetes; Vancomycin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / toxicity*
  • Cytokines / blood
  • Diabetes Mellitus, Experimental / chemically induced*
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 1 / chemically induced*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / pathology
  • Endocrine Disruptors / toxicity*
  • Female
  • Glucose Tolerance Test
  • Immunoglobulin G / blood
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Inbred NOD
  • Organ Specificity
  • Phenols / toxicity*
  • Sex Characteristics*
  • Spleen / drug effects
  • Spleen / immunology
  • Spleen / pathology


  • Benzhydryl Compounds
  • Cytokines
  • Endocrine Disruptors
  • Immunoglobulin G
  • Phenols
  • bisphenol A