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Abstract
Type 1 diabetes (T1D) is an autoimmune disease that has been linked to dysbiosis of the gut microbiota. Bisphenol A (BPA), an endocrine disrupter (ED) with widespread human exposure, can modulate the immune system and alter the gut microbiome, which may be contributing to the increasing T1D incidence worldwide. Bisphenol S (BPS), another ED, is the most common replacement of BPA in polycarbonate plastics and epoxy resins resulting in widespread human exposure, but toxicological research is scarce and no studies have determined BPSs effect on T1D. The current research objective was to determine if BPA and BPS exposure modulates T1D susceptibility through alteration of the gut microbiome and immune responses, and whether exacerbation or protection from T1D development depends on exposure window and sex. Here, we show BPA accelerated T1D incidence and/or increased blood glucose levels in females exposed during the adult or juvenile period, but protected adult males and offspring (both males and females) from T1D. For BPA exposure, several pro-inflammatory immune factors including macrophages and IFN- were increased in adult females, and several bacteria that exacerbate (e.g. Bacteroidetes) T1D were increased. Likewise, pro-inflammatory bacteria were increased in juvenile females, whereas effects on immunity were not clear. Conversely, female offspring had increased anti-inflammatory immune factors with T1D protection. As for adult males, a general decrease in anti-inflammatory (e.g. Akkermansia) and pro-inflammatory (e.g. Bacilli) microbes resulted, while male offspring had minimal effects. For BPS, varied glucose levels based on sex and diet were observed with adult females showing protection from T1D and males on a soy-based diet having insulin resistance. However, minimal effect was observed in immune cell populations, which suggests other mechanisms should be investigated. Additionally, exposing males on a phytoestrogen-free diet resulted in tolerance tests and splenocyte populations showing a trend of protection from T1D, while a high-fat diet varied tolerance based on exposure length. Overall, BPA exposure showed unique sex- and age-dependent effects on T1D, which are likely due to immunomodulation and microbiome alteration. Opposite BPA, BPS exposure on a soy-based diet protected adult exposed females from T1D and had adverse effects in males with diet-dependent effects.