Prioritizing Environmental Chemicals for Obesity and Diabetes Outcomes Research: A Screening Approach Using ToxCast™ High-Throughput Data

Abstract

Background:Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCast™ high-throughput screening (HTS) program.Objectives:Our aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high-throughput screening data.Methods:We identified ToxCast™ assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and β cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest.Discussion:The results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCast™ data will also help assess the predictive utility of this HTS platform.Conclusions:More research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses.Citation:Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. 2016. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCast™ high-throughput data. Environ Health Perspect 124:1141–1154; http://dx.doi.org/10.1289/ehp.1510456

Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups

“…ToxPi provides a dimensionless index score that integrates multiple, different in vitro assay results and displays them visually. Within each subset of endpoints (“slice”), data are transformed into ToxPi slice-wise scores for all compounds using methods detailed in publications describing applications of the approach and in documentation associated with the software package (Grimm et al, 2016; Auerbach et al, 2016; Sirenko et al, 2013; Rager et al, 2016). Briefly, within each individual slice for a given chemical, the distance from the origin represents the relative chemical-elicited activity of the component in vitro assay endpoints.…”

“…Thus, all ToxPi results (Figure 3 and Figure 4) consider the same, full set of reference chemicals to set slice lengths that are summed into overall profile scores. For complete details, the full source code is freely-available with (Auerbach et al, 2016) and can be used with the Supplemental Files cited in Section 2.2.1.…”

High-Content Analysis Provides Mechanistic Insights into the Testicular Toxicity of Bisphenol A and Selected Analogues in Mouse Spermatogonial Cells

“…The Environmental Protection Agency has initiated a ToxCast project integrating in vitro high-content and high-throughput toxicity assessment to characterize the toxicological profiles of thousands of chemicals (Auerbach et al, 2016;Karmaus et al, 2016;Kavlock et al, 2012;Paul Friedman et al, 2016). High-content analysis (HCA) has been demonstrated to be particularly useful for toxicity testing and prediction as it enables measurements of multiple, early toxicological mechanisms by characterizing co-expression of multiple molecules, as well as quantification and visualization of the spatial and temporal dynamic processes of cellular events.…”

Unconventional oil and gas chemicals and wastewater-impacted water samples promote adipogenesis via PPARγ-dependent and independent mechanisms in 3T3-L1 cells

“…Recent work has suggested elevated body burdens of UOG chemicals in humans living near these sites (Crowe et al, 2016; Caron-Beaudoin et al, 2018), though working out the potential oral, dermal, and inhalation exposure routes will take more directed work in future studies. Given the extremely high societal costs of obesity and associated metabolic health disease (Hammond and Levine, 2010; Legler et al, 2015), as well as the growing understanding of environmental metabolic disruptors (Kassotis et al, 2017a; Heindel et al, 2015; Auerbach et al, 2016; Heindel et al, 2017), future studies should more specifically assess potential metabolic health concerns near UOG operations.…”

“…Legler et al estimated the economic costs attributable to five EDCs with the strongest epidemiological evidence from obesity, diabetes, and associated costs at €18–29 billion per year in the European Union (Legler et al, 2015). Reports of potential metabolic disruption caused by environmental chemicals have been increasing, as the means to sensitively and inexpensively assess these outcomes have proliferated (Kassotis et al, 2017a; Heindel et al, 2015; Auerbach et al, 2016; Heindel et al, 2017). One of these tools, 3T3–L1 mouse pre-adipocytes, is commonly used to assess putative metabolic disruptors in vitro and has been demonstrated to accurately predict metabolic disruption in vivo (Angle et al, 2013; Chamorro-Garcia et al, 2013; Li et al, 2011; Masuno et al, 2005).…”