Endocrine-Mediated Mechanisms of Metabolic Disruption and New Approaches to Examine the Public Health Threat.

Obesity and metabolic disorders are of great societal concern and generate substantial human health care costs globally. Interventions have resulted in only minimal impacts on disrupting this worsening health trend, increasing attention on putative environmental contributors. Exposure to numerous environmental contaminants have, over decades, been demonstrated to result in increased metabolic dysfunction and/or weight gain in cell and animal models, and in some cases, even in humans. There are numerous mechanisms through which environmental contaminants may contribute to metabolic dysfunction, though certain mechanisms, such as activation of the peroxisome proliferator activated receptor gamma or the retinoid x receptor, have received considerably more attention than less-studied mechanisms such as antagonism of the thyroid receptor, androgen receptor, or mitochondrial toxicity. As such, research on putative metabolic disruptors is growing rapidly, as is our understanding of molecular mechanisms underlying these effects. Concurrent with these advances, new research has evaluated current models of adipogenesis, and new models have been proposed. Only in the last several years have studies really begun to address complex mixtures of contaminants and how these mixtures may disrupt metabolic health in environmentally relevant exposure scenarios. Several studies have begun to assess environmental mixtures from various environments and study the mechanisms underlying their putative metabolic dysfunction; these studies hold real promise in highlighting crucial mechanisms driving observed organismal effects. In addition, high-throughput toxicity databases (ToxCast, etc.) may provide future benefits in prioritizing chemicals for testing, particularly once the causative molecular mechanisms promoting dysfunction are better understood and expert critiques are used to hone the databases. In this review, we will review the available literature linking metabolic disruption to endocrine-mediated molecular mechanisms, discuss the novel application of environmental mixtures and implications for metabolic health, and discuss the putative utility of applying high-throughput toxicity databases to answering complex organismal health outcome questions.