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On September 7 and 8, 2022, Healthy Environment and Endocrine Disruptors Strategies, an Environmental Health Sciences program, convened a scientific workshop of relevant stakeholders involved in obesity, toxicology, or obesogen research to review the state of the science regarding the role of obesogenic chemicals that might be contributing to the obesity pandemic. The workshops objectives were to examine the evidence supporting the hypothesis that obesogens contribute to the etiology of human obesity; to discuss opportunities for improved understanding, acceptance, and dissemination of obesogens as contributors to the obesity pandemic; and to consider the need for future research and potential mitigation strategies. This report details the discussions, key areas of agreement, and future opportunities to prevent obesity. The attendees agreed that environmental obesogens are real, significant, and a contributor at some degree to weight gain at the individual level and to the global obesity and metabolic disease pandemic at a societal level; moreover, it is at least, in theory, remediable.

Obesity is a multifactorial disease with both genetic and environmental components. The prevailing view is that obesity results from an imbalance between energy intake and expenditure caused by overeating and insufficient exercise. We describe another environmental element that can alter the balance between energy intake and energy expenditure: obesogens. Obesogens are a subset of environmental chemicals that act as endocrine disruptors affecting metabolic endpoints. The obesogen hypothesis posits that exposure to endocrine disruptors and other chemicals can alter the development and function of the adipose tissue, liver, pancreas, gastrointestinal tract, and brain, thus changing the set point for control of metabolism. Obesogens can determine how much food is needed to maintain homeostasis and thereby increase the susceptibility to obesity. The most sensitive time for obesogen action is in utero and early childhood, in part via epigenetic programming that can be transmitted to future generations. This review explores the evidence supporting the obesogen hypothesis and highlights knowledge gaps that have prevented widespread acceptance as a contributor to the obesity pandemic. Critically, the obesogen hypothesis changes the narrative from curing obesity to preventing obesity.

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants previously associated with elevated liver enzymes in human cohorts and steatotic liver disease in animal models. We aimed to evaluate the associations between PFAS exposures, and liver enzymes and vibration controlled transient elastography (VCTE) biomarkers of metabolic dysfunction associated steatotic liver disease (MASLD) in adult National Health and Nutrition Examination Survey (NHANES) 2017 to 2018. VCTE was determined by FibroScan. Serum PFAS (n  = 14), measured by mass spectrometry, were analyzed individually and by principal component (PC). Univariate and multivariable associations were determined between PFAS exposures and liver disease outcome variables: alanine aminotransferase (ALT), controlled attenuation parameter (CAP), liver stiffness measurement (LSM), FibroScan-based Score (FAST), using R. About 1,400 participants including 50% women with a mean age of 48 ± 19 years and a mean BMI of 29 ± 7 kg/m2 were analyzed. Four PFAS clustered to PC1, whereas 3 PFAS clustered to PC2. PC1 was significantly associated with ALT (β = 0.028), CAP (β = 0.041), LSM (β = 0.025), and FAST (β = 0.198) in univariate analysis. Individual PFAS exposures were oftentimes inversely associated with these measurements in multivariate analysis. In adult NHANES 2017–2018, PFAS may not be a significant burden for MASLD, because of the inconsistent associations between the environmental PFAS exposures and biomarkers of liver steatosis, inflammation, and fibrosis. More data are required to better understand the relationships between PFAS exposures and liver disease. [ABSTRACT FROM AUTHOR]

Background: Funding agencies, publishers, and other stakeholders are pushing environmental health science investigators to improve data sharing; to promote the findable, accessible, interoperable, and reusable (FAIR) principles; and to increase the rigor and reproducibility of the data collected. Accomplishing these goals will require significant cultural shifts surrounding data management and strategies to develop robust and reliable resources that bridge the technical challenges and gaps in expertise. Objective: In this commentary, we examine the current state of managing data and metadata--referred to collectively as (meta)data--in the experimental environmental health sciences. We introduce new tools and resources based on in vivo experiments to serve as examples for the broader field. Methods: We discuss previous and ongoing efforts to improve (meta)data collection and curation. These include global efforts by the Functional Genomics Data Society to develop metadata collection tools such as the Investigation, Study, Assay (ISA) framework, and the Center for Expanded Data Annotation and Retrieval. We also conduct a case study of in vivo data deposited in the Gene Expression Omnibus that demonstrates the current state of in vivo environmental health data and highlights the value of using the tools we propose to support data deposition. Discussion: The environmental health science community has played a key role in efforts to achieve the goals of the FAIR guiding principles and is well positioned to advance them further. We present a proposed framework to further promote these objectives and minimize the obstacles between data producers and data scientists to maximize the return on research investments. https://doi.org/10.1289/EHP11484, Introduction Transparent and comprehensive data sharing is a laudable but challenging goal in any research domain, including the environmental health sciences. Major failings in research reproducibility often result in wasted [...]

Background: Alcohol use disorder (AUD) with chronic and heavy alcohol consumption causes alcohol‐associated liver disease (ALD). Early‐stage ALD exhibits dyshomeostasis of zinc. We investigated the role of zinc deficiency in gut‐barrier dysfunction, proinflammatory response, hepatocyte injury, and death, as well as potential sex differences in AUD patients. Methods: Thirty‐nine male and female AUD patients were grouped by normal [≥71 μg/dL (Group 1, number (n) = 26)] and low [<71 μg/dL (Group 2, n = 13)] serum zinc levels. Demographics, alcohol intake markers [Lifetime Drinking History (LTDH), heavy drinking days in the past 90‐days (HDD90), total drinks in the past 90‐days (TD90), number of drinking days in the past 90‐days (NDD90), average drinks per day in the past 90 days (AvgDPD90)] were collected. Blood samples were tested for complete blood count (CBC), comprehensive metabolic panel (CMP), coagulation markers, gut‐barrier dysfunction markers, cytokines, and hepatocyte death markers. Results: Group 2 females exhibited lower LTDH than Group 2 males (p = 0.028), but higher recent drinking. Aspartate transaminase: alanine transaminase (AST:ALT) ratio was higher (p = 0.049) in Group 2 males compared to Group 1 males. Overall, Group 2 showed threefold higher interleukin 8 (IL‐8) levels than Group 1 (p = 0.92); these were sevenfold higher in Group 2 females than Group 1 females. Group 2 females also had higher K18M65, but lower K18M30 than Group 1 females. Necrotic type of cell death (K18M65) was well‐described only in Group 2 by the arrangement of lipopolysaccharide (LPS), soluble cluster of differentiation 14 (sCD14), and tumor necrosis factor alpha (TNF‐α) (R2 = 0.633, p = 0.037). Conclusion: Our findings demonstrated the role of the gut‐immune‐liver axis in describing hepatocyte injury and death in zinc‐deficient AUD patients. These patients represented an arrangement of gut‐barrier dysfunction and an exacerbated immune response. Shift in the cell‐death mechanism from apoptosis in zinc‐replete females to necrosis in zinc‐deficient females suggests a subclinical to clinical transition of ALD associated with zinc status. [ABSTRACT FROM AUTHOR]

Background: Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress. Objectives: We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort. methods: Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed. Results: The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor [alpha] were well integrated within the top identified networks. Discussion: These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467, Introduction Environmental hepatology is an emerging field focused on the environmental contribution to liver health and disease (Cave 2020). Pollution exposures have been associated with a variety of liver histopathologies, [...]