| Summary: | The past several decades have witnessed a dramatic expansion in the rates of metabolic disease, most prominently the obesity and diabetes epidemics. While metabolic disease is undoubtedly driven by increased caloric intake and decreased physical activity, exposure to endocrine disrupting chemicals (EDCs) has been implicated as a causal factor in the development of metabolic disease. EDCs are exogenous compounds capable of modulating endogenous hormonal axes, with some compounds capable of interfering with metabolic pathways. Prior work identified the fungicide and booster biocide tolylfluanid (TF) as a potent EDC with the capacity to induce adipocyte differentiation and impair adipocyte insulin signaling through stimulation of the glucocorticoid receptor (GR). The present studies seek to expand upon these data by investigating the outcomes of dietary exposure to TF across the lifespan, with the hypothesis that TF disrupts energy metabolism through aberrant stimulation of the GR, and that disruptions in global metabolic homeostasis are driven by modulation of adipose physiology. When male mice were provided a diet supplemented with 100ppm TF, they exhibited several metabolic changes that mirror the metabolic syndrome, including augmented visceral adiposity, glucose intolerance, global and cellular insulin resistance, and disruptions in circadian rhythms. Importantly, gene set enrichment analysis identified an enrichment of GR-dependent genes in the adipose tissue of exposed mice. Next, investigating the interaction of TF with diet identified novel differences in the outcomes of exposure depending on the background macronutrient content of the diet. Finally, developmental exposure to TF during prenatal and early postnatal life was found to modulate insulin-glucose homeostasis in adult life, in a sex-dependent manner. Taken together, these findings identify TF as a novel metabolic disruptor in vivo, and support prior studies identifying TF as a potent environmental glucocorticoid.
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