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

Abstract

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 in vivo 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 in vivo metabolic health, and discuss the putative utility of applying high-throughput toxicity databases to answering complex organismal health outcome questions.

Keywords: 3T3-L1; adipogenesis; diabetes; diabetogen; endocrine disrupting chemicals; obesity; obesogen.

Figure 1

Representative EDCs Capable of Affecting Adipogenesis. Representative endocrine disrupting chemicals (EDCs) capable of affecting adipogenesis and/or metabolic health through the specified nuclear receptor pathways listed above. Gross circle size intended to express a general sense of the reported research into assessing these varying mechanisms; for example, PPARγ, RXRα, and GR have previously received the bulk of the research, whereas others have received less. Agonists for the receptors are depicted with a (+) following the chemicals, whereas antagonists are denoted with the (−). Standard positive and negative control chemicals for each receptor (for evaluating these pathways) are bolded to distinguish from the other EDC examples. PPAR, peroxisome proliferator activated receptor; RXR, retinoid X receptor; AR, androgen receptor; ER, estrogen receptor; CAR, constitutive androstane receptor; TR, thyroid receptor; FXR, farnesoid X receptor; LXR, liver X receptor; GR, glucocorticoid receptor.

Figure 2

Mechanisms of EDC Exposure and Potential Human Metabolic Health Effects. Graphical depiction of the potential sources and exposure pathways for humans to endocrine disrupting chemicals (EDCs), the molecular mechanisms related to metabolic health through which these EDCs may act to drive specific mechanistic effects, all of which may contribute to potential adverse health risks for humans. Effects reported are representative and are not comprehensive to all molecular mechanisms and mechanistic effects.

Figure 3

Utility of Utilizing Environmental Mixtures for Human Health Assessments. Graphical depiction comparing individual chemicals and environmental mixtures for the assessment of potential human health effects. While environmental mixtures have less use in identifying causative chemicals in all cases (though tools like effect directed analysis (EDA) and toxicity identification evaluation (TIE) can be used to elucidate this), these mixtures are more relevant in reflecting the suite of chemicals that people are exposed to on a daily basis than utilizing single chemicals alone, and more often reflect actual environmental exposure concentrations. In this figure, the blue lines indicate positive relationships and the red lines indicate difficulty for single chemicals or mixtures in assessing the related outcome.