Exposure to Persistent Organic Pollutants (POPs) and Their Relationship to Hepatic Fat and Insulin Insensitivity among Asian Indian Immigrants in the United States

Merrill, Michele A. La; Johnson, Caitlin L; Smith, Martyn T.; Kandula, Namratha R.; Macherone, Anthony; Pennell, Kurt D.; Kanaya, Alka M.

doi:10.1021/acs.est.9b03373

Cited by 38 publications

(15 citation statements)

References 103 publications

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“…Increasing epidemiological and experimental evidence suggests that exposure to some environmental contaminants could contribute to NAFLD progression [96][97][98][99]. Pesticides, insecticides, fungicides, and herbicides have demonstrated hepatotoxic effects by modulating lipid metabolism, inflammation, and oxidative stress [100].…”

Section: Environmental Factorsmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

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Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.

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Section: Environmental Factorsmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

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“…Tissue concentrations of o,p'-DDT, p,p'-DDT, o,p'-DDE, and p,p'-DDE were measured in BAT from 4-monthold mice using gas chromatography (GC)-MS following methods described previously (2). Brie y, 30 mg ash frozen BAT samples (n = 3/group) were extracted using a QuEChERS-based extraction with 1:1:1 hexane:acetone:dichloromethane.…”

Section: Ddt Metabolite Concentration Quanti Cationmentioning

confidence: 99%

“…Further, exposure is ongoing in many parts of the world because of the recommended use of DDT for malaria control by the World Health Organization, due in part to widespread anti-malarial drug resistance (1). For example, the median levels of DDT and DDE detected in the blood of immigrants to the USA from India, where DDT continues to be manufactured, exceeded the 95th percentile of DDT and DDE levels in the general U.S. population, and was signi cantly associated with their increased body mass index and increased odds of obesity in a 2019 study (2).…”

Section: Introductionmentioning

confidence: 99%

Developmental Exposure to DDT or DDE Alters Sympathetic Innervation of Brown Adipose in Adult Female Mice

vonderEmbse

Elmore

Jackson

et al. 2020

Preprint

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Background: Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis. Methods: Pregnant C57BL/6J mice were exposed by oral gavage to environmentally relevant concentrations of DDT (1.7 mg/kg) or DDE (1.31 mg/kg) from gestational day 11.5 to postnatal day 5, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated.Results: We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDT or DDE. Perinatal DDT exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDT nor DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDT-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDT, but not DDE, and 48% and 43% fewer synapses in stellate ganglia of mice exposed to either DDT or DDE, respectively, compared to control. Conclusions: These data demonstrate that perinatal DDT and DDE exposure impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

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“…Exposure to environmental metabolism-disrupting chemicals (MDCs) contributes to the development and propagation of liver steatosis and hepatotoxicity [1][2][3][4][5][6][7]. The liver is one of the organs most susceptible to drug toxicity, as evidenced from the fact that drug-induced liver injury (DILI) accounts for more than 50% of acute liver failure in humans [8,9].…”

Section: Introductionmentioning

confidence: 99%

Prediction Model of Aryl Hydrocarbon Receptor Activation by a Novel QSAR Approach, DeepSnap–Deep Learning

et al. 2020

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that senses environmental exogenous and endogenous ligands or xenobiotic chemicals. In particular, exposure of the liver to environmental metabolism-disrupting chemicals contributes to the development and propagation of steatosis and hepatotoxicity. However, the mechanisms for AhR-induced hepatotoxicity and tumor propagation in the liver remain to be revealed, due to the wide variety of AhR ligands. Recently, quantitative structure–activity relationship (QSAR) analysis using deep neural network (DNN) has shown superior performance for the prediction of chemical compounds. Therefore, this study proposes a novel QSAR analysis using deep learning (DL), called the DeepSnap–DL method, to construct prediction models of chemical activation of AhR. Compared with conventional machine learning (ML) techniques, such as the random forest, XGBoost, LightGBM, and CatBoost, the proposed method achieves high-performance prediction of AhR activation. Thus, the DeepSnap–DL method may be considered a useful tool for achieving high-throughput in silico evaluation of AhR-induced hepatotoxicity.

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Exposure to Persistent Organic Pollutants (POPs) and Their Relationship to Hepatic Fat and Insulin Insensitivity among Asian Indian Immigrants in the United States

Cited by 38 publications

References 103 publications

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Developmental Exposure to DDT or DDE Alters Sympathetic Innervation of Brown Adipose in Adult Female Mice

Prediction Model of Aryl Hydrocarbon Receptor Activation by a Novel QSAR Approach, DeepSnap–Deep Learning

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