Type 2 diabetes disproportionately afflicts African-Americans, Latinx communities, and people with low income in the U.S. due to complex environmental influences. Despite the history of environmental inequality in the U.S, the potential contribution of endocrine-disrupting chemicals (EDCs) to racial/ethnic and socioeconomic differences in diabetes risk is not known. Evidence from recent decades gathered from the present comprehensive literature review showing uneven socioeconomic and racial/ethnic EDC exposures raises the possibility that EDCs are underappreciated contributors to diabetes disparities. Notably, EDC exposures during critical windows of development can program metabolic disease risk in a sex-specific way. Importantly, EDCs that modulate glucocorticoid receptor (GR) signaling are an understudied class of environmental pollutants of likely public health significance given that glucocorticoids regulate the development of tissues that control glucose homeostasis. The present studies examined the impact of perinatal exposure to the fungicide tolylfluanid (TF) on metabolic physiology in adult mouse offspring to understand how GR-disrupting EDCs can misprogram metabolism in a sex-specific manner. C57BL/6J dams received standard rodent chow or the same diet containing 67 mg/kg TF. Female offspring exhibited reduced glucose tolerance, markedly enhanced systemic insulin sensitivity, reduced adiposity, and normal gluconeogenic capacity during adulthood. In contrast, male offspring exhibited impaired glucose tolerance with unchanged insulin sensitivity, no differences in adiposity, and increased gluconeogenic capacity. These findings indicating that perinatal TF exposure programs metabolism in a sex-specific manner imply that exposure to other GR-modulating EDCs may elicit similar effects, and suggest that unequal exposures to GR-modulating EDCs may program metabolic disease risk differently by sex in exposed populations.




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