The Ah receptor: adaptive metabolism, ligand diversity, and the xenokine model

Author Posting. © American Chemical Society, 2020. This is an open access article published under an ACS AuthorChoice License. The definitive version was published in Chemical Research in Toxicology, 33(4), (2020): 860-879, doi:10.1021/acs.chemrestox.9b00476.The Ah receptor (AHR) has been studied for almost five decades. Yet, we still have many important questions about its role in normal physiology and development. Moreover, we still do not fully understand how this protein mediates the adverse effects of a variety of environmental pollutants, such as the polycyclic aromatic hydrocarbons (PAHs), the chlorinated dibenzo-p-dioxins (“dioxins”), and many polyhalogenated biphenyls. To provide a platform for future research, we provide the historical underpinnings of our current state of knowledge about AHR signal transduction, identify a few areas of needed research, and then develop concepts such as adaptive metabolism, ligand structural diversity, and the importance of proligands in receptor activation. We finish with a discussion of the cognate physiological role of the AHR, our perspective on why this receptor is so highly conserved, and how we might think about its cognate ligands in the future.This review is dedicated in memory of the career of Alan Poland, one of the truly great minds in pharmacology and toxicology. This work was supported by the National Institutes of Health Grants R35-ES028377, T32-ES007015, P30-CA014520, P42-ES007381, and U01-ES1026127, The UW SciMed GRS Program, and The Morgridge Foundation. The authors would like to thank Catherine Stanley of UW Media Solutions for her artwork

The association between neighborhood economic hardship, the retail food environment, fast food intake, and obesity: findings from the Survey of the Health of Wisconsin

Background: Neighborhood-level characteristics such as economic hardship and the retail food environment are assumed to be correlated and to influence consumers' dietary behavior and health status, but few studies have investigated these different relationships comprehensively in a single study. This work aims to investigate the association between neighborhood-level economic hardship, the retail food environment, fast food consumption, and obesity prevalence. Methods: Linking data from the population-based Survey of the Health of Wisconsin (SHOW, n = 1,570, 2008-10) and a commercially available business database, the Wisconsin Retail Food Environment Index (WRFEI) was defined as the mean distance from each participating household to the three closest supermarkets divided by the mean distance to the three closest convenience stores or fast food restaurants. Based on US census data, neighborhood-level economic hardship was defined by the Economic Hardship Index (EHI). Relationships were analyzed using multivariate linear and logistic regression models. Results: SHOW residents living in neighborhoods with the highest economic hardship faced a less favorable retail food environment (WRFEI = 2.53) than residents from neighborhoods with the lowest economic hardship (WRFEI = 1.77; p-trend < 0.01). We found no consistent or significant associations between the WRFEI and obesity and only a weak borderline-significant association between access to fast food restaurants and self-reported fast food consumption (≥2 times/week, OR = 0.59-0.62, p = 0.05-0.09) in urban residents. Participants reporting higher frequency of fast food consumption (≥2 times vs. <2 times per week) were more likely to be obese (OR = 1.35, p = 0.06). Conclusion: This study indicates that neighborhood-level economic hardship is associated with an unfavorable retail food environment. However inconsistent or non-significant relationships between the retail food environment, fast food consumption, and obesity were observed. More research is needed to enhance methodological approaches to assess the retail food environment and to understand the complex relationship between neighborhood characteristics, health behaviors, and health outcomes

Using recursive feature elimination in random forest to account for correlated variables in high dimensional data

Abstract Background Random forest (RF) is a machine-learning method that generally works well with high-dimensional problems and allows for nonlinear relationships between predictors; however, the presence of correlated predictors has been shown to impact its ability to identify strong predictors. The Random Forest-Recursive Feature Elimination algorithm (RF-RFE) mitigates this problem in smaller data sets, but this approach has not been tested in high-dimensional omics data sets. Results We integrated 202,919 genotypes and 153,422 methylation sites in 680 individuals, and compared the abilities of RF and RF-RFE to detect simulated causal associations, which included simulated genotype–methylation interactions, between these variables and triglyceride levels. Results show that RF was able to identify strong causal variables with a few highly correlated variables, but it did not detect other causal variables. Conclusions Although RF-RFE decreased the importance of correlated variables, in the presence of many correlated variables, it also decreased the importance of causal variables, making both hard to detect. These findings suggest that RF-RFE may not scale to high-dimensional data

Neighborhood Perceptions and Cumulative Impacts of Low Level Chronic Exposure to Fine Particular Matter (PM2.5) on Cardiopulmonary Health

Adverse perceptions of neighborhood safety, aesthetics and quality including access to resources can induce stress and may make individuals more sensitive to cardiopulmonary effects of air pollution exposure. Few studies have examined neighborhood perceptions as important and modifiable non-chemical stressors of the built environment that may exacerbate effects of air pollution on cardiopulmonary health outcomes, particularly among general population based cohorts. This study examined associations between low-level chronic exposure to fine particulate matter (PM2.5) and cardiopulmonary health, and the potential mediating or modifying effects of adverse neighborhood perceptions. Using data from the Survey of the Health of Wisconsin (SHOW), 2230 non-asthmatic adults age 21–74 were included in the analyses. The overall goals of this study were to assess if individuals who experience stress from neighborhood environments in which they live were more sensitive to low levels of fine particular matter (PM2.5 μg/m3). Demographic predictors of air pollution exposure included younger age, non-White race, lower education and middle class income. After adjustments, objective lung function measures (FEV1 and FEV1 to FVC ratio) were the only cardiopulmonary health indicators significantly associated with chronic three-year annual averages of PM2.5. Among all non-asthmatics, a ten unit increase in estimated three year annual average PM2.5 exposure was significantly associated with lower forced expiratory volume (L) in one second FEV1 (β = −0.40 μg/L; 95% CI −0.45, −0.06). Among all individuals, adverse perceptions of the neighborhood built environment did not appear to statistically moderate or mediate associations. However, stratified analysis did reveal significant associations between PM2.5 and lung function (FEV1) only among individuals with negative perceptions and increased reports of neighborhood stressors. These findings included individuals who felt their neighborhoods were poorly maintained (β = −0.82; 95% CI −1.35, −0.28), experienced stress from crime (β = −0.45; 95% CI −0.94, 0.04) or reported neighborhood is not well maintained (β = −1.13, CI −2.04, −0.24). These significant associations were similar for FEV1 to FVC ratio. Multi-pronged approaches addressing both neighborhood built environment aesthetics and air pollution regulation may be necessary to protect vulnerable and susceptible individuals and reduce persistent inequalities

Comparison of cricket diet with peanut-based and milk-based diets in the recovery from protein malnutrition in mice and the impact on growth, metabolism and immune function.

Some evidence suggests that edible insects could be used to treat malnutrition following protein deficiency. However, additional studies are needed to better assess the potential of edible insects as a therapeutic food supplement and their long-term impact on recovery from malnutrition. The goals of this study were to investigate the effectiveness of a cricket-based diet in recovery from protein-malnutrition in early life, and to compare cricket protein to more traditional sources used for food fortification and supplementation. Protein-malnutrition was induced by administration of an isocaloric hypoprotein diet (5% protein calories) in young male mice for two weeks during puberty, followed by a six-week recovery period using a cricket-, peanut- or milk-based diet. We examined the impact of protein-malnutrition and subsequent recovery on body weight, growth and select biomarkers of inflammation and metabolism. Protein-malnutrition resulted in growth retardation, downregulation of inflammatory markers in spleen tissue, decreased levels of serum triglycerides, and elevated serum levels of leptin and adiponectin. The cricket-based diet performed equally well as the peanut- and milk-based diets in body weight recovery, but there were differences in immune and metabolic markers among the different recovery diets. Results suggest edible crickets may provide an alternative nutrient-dense protein source with relatively low environmental demands for combating the effects of early-life malnutrition compared to more traditional supplementation and fortification sources. Additional investigations are needed to examine the short and long term impacts of different recovery diets on metabolism and immune function

Adopting a "Compound" Exposome Approach in Environmental Aging Biomarker Research: A Call to Action for Advancing Racial Health Equity.

BackgroundIn June 2020, the National Academies of Sciences, Engineering, and Medicine hosted a virtual workshop focused on integrating the science of aging and environmental health research. The concurrent COVID-19 pandemic and national attention on racism exposed shortcomings in the environmental research field's conceptualization and methodological use of race, which have subsequently hindered the ability of research to address racial health disparities. By the workshop's conclusion, the authors deduced that the utility of environmental aging biomarkers-aging biomarkers shown to be specifically influenced by environmental exposures-would be greatly diminished if these biomarkers are developed absent of considerations of broader societal factors-like structural racism-that impinge on racial health equity.ObjectivesThe authors reached a post-workshop consensus recommendation: To advance racial health equity, a "compound" exposome approach should be widely adopted in environmental aging biomarker research. We present this recommendation here.DiscussionThe authors believe that without explicit considerations of racial health equity, people in most need of the benefits afforded by a better understanding of the relationships between exposures and aging will be the least likely to receive them because biomarkers may not encompass cumulative impacts from their unique social and environmental stressors. Employing an exposome approach that allows for more comprehensive exposure-disease pathway characterization across broad domains, including the social exposome and neighborhood factors, is the first step. Exposome-centered study designs must then be supported with efforts aimed at increasing the recruitment and retention of racially diverse study populations and researchers and further "compounded" with strategies directed at improving the use and interpretation of race throughout the publication and dissemination process. This compound exposome approach maximizes the ability of our science to identify environmental aging biomarkers that explicate racial disparities in health and best positions the environmental research community to contribute to the elimination of racial health disparities. https://doi.org/10.1289/EHP8392

Environmental exposures during windows of susceptibility for breast cancer: a framework for prevention research

Background The long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman’s life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention. Main text Despite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland’s structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals—including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols—and metals. We outline ways in which ongoing transdisciplinary BCERP projects incorporate animal research and human epidemiologic studies in close partnership with community organizations and communication scientists to identify research priorities and effectively translate evidence-based findings to the public and policy makers. Conclusions An integrative model of breast cancer research is needed to determine the impact and mechanisms of action of endocrine disruptors at different WOS. By focusing on environmental chemical exposure during specific WOS, scientists and their community partners may identify when prevention efforts are likely to be most effective