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Exposure to a persistent organic pollutant mixture and sex-specific steatotic liver disease

ABSTRACT: A 2DLC-(TMTPro)-MS workflow was used to examine hepatic exposure to persistent organic pollutants (POPs) with steatotic liver disease (SLD). The goal was to determine the sex-specific impact of POPs on SLD and identify underlying sex-specific mechanisms. Male and female C57BL/6 mice were fed either a western (WD) or control diet (CD) and exposed to vehicle control or a POP mixture (PCB 126 and chlordane) over a 12-week period. A second group of intact female or ovariectomized (OVX) mice were exposed to the same POP mixture or vehicle control for 2 weeks. Compared to their diet- and sex-matched controls, WD-fed female mice exposed to the POP mixture exhibited steatosis and these observations were absent in males. Chemical exposure, irrespective of sex and diet, activated hepatic xenobiotic receptors, namely the AHR (Cyp1a1/Cyp1a2 induction) and CAR (Cyp1b10 induction), more robust CAR activation was observed in CD-fed females. This group also showed decreased liver gene expression for estrogen sulfotransferase (Sult1e1), a key enzyme in estrogen metabolism. Female mice exposed to the POP mixture were more susceptible to toxicant-associated SLD. Our findings emphasized the significance of considering biological sex in assessing disease risk

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Michael L. Merchant, PhD

PROVIDER: MSV000098555 | MassIVE | Fri Jul 18 06:59:00 BST 2025

REPOSITORIES: MassIVE

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Project description:<div>BACKGROUND: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of pesticides using individual molecules, often at non-relevant doses or in combination with other risk factors such as high fat diets.<br></div><div>OBJECTIVES: We aimed to evaluate, in mice, the metabolic consequences of chronic dietary exposure to a pesticide mixture at non-toxic doses, relevant to consumers’ risk assessment.<br></div>METHODS: A mixture of six pesticides commonly used in France i.e. boscalid, captan, chlorpyrifos, thiofanate, thiacloprid, and ziram was incorporated in a standard chow diet, at doses exposing mice to the acceptable daily intake (ADI) of each pesticide. Wild-type (WT) and Constitutive Androstane Receptor knock-out (CAR-/-) C57Bl6/J male and female mice were exposed for 52 weeks. We assessed metabolic parameters (body-weight, food and water consumption, glucose tolerance, urinary metabolome) throughout the experiment. At the end of the experiment, we evaluated liver metabolism (histology, transcriptomics, metabolomics) and pesticide detoxification using LC/MS.<br>RESULTS: In males, pesticide exposure increased body weight and adiposity and induced hepatic steatosis and glucose intolerance. Exposed females exhibited fasted hyperglycaemia, hepatic oxidative stress and perturbations of gut microbiota-related urinary metabolites. The Constitutive Androstane Receptor is involved in the sexually dimorphic response to pesticide exposure.<br><div> CONCLUSIONS: We show for the first time the sexually dimorphic obesogen and diabetogen effects of a chronic dietary exposure <br>to a realistic mixture of pesticides, which are partially mediated through CAR. This raises questions about the relevance of ADI for <br>individual pesticides when present in a mixture.</div><div><br></div><div><b>Untargeted urine, plasma and liver NMR assay</b> protocols and data are reported in the current study <b>MTBLS602</b>.<br><br><b>Untargeted urine UPLC-MS assay</b> protocols and data associated to this study are reported in <a href="https://www.ebi.ac.uk/metabolights/MTBLS596"><b>MTBLS596</b></a>.<br></div><div><br></div>

Project description:<div>BACKGROUND: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of pesticides using individual molecules, often at non relevant doses or in combination with other risk factors such as high fat diets.<br></div><div>OBJECTIVES: We aimed to evaluate, in mice, the metabolic consequences of chronic dietary exposure to a pesticide mixture at non-toxic doses, relevant to consumers’ risk assessment.<br></div> METHODS: A mixture of six pesticides commonly used in France i.e. boscalid, captan, chlorpyrifos, thiofanate, thiacloprid, and ziram was incorporated in a standard chow diet, at doses exposing mice to the acceptable daily intake (ADI) of each pesticide. Wild-type (WT) and Constitutive Androstane Receptor knock-out (CAR-/-) C57Bl6/J male and female mice were exposed for 52 weeks. We assessed metabolic parameters (body-weight, food and water consumption, glucose tolerance, urinary metabolome) throughout the experiment. At the end of the experiment, we evaluated liver metabolism (histology, transcriptomics, metabolomics) and pesticide detoxification using LC/MS.<br>RESULTS: In males, pesticide exposure increased body weight and adiposity and induced hepatic steatosis and glucose intolerance. Exposed females exhibited fasted hyperglycaemia, hepatic oxidative stress and perturbations of gut microbiota-related urinary metabolites. The Constitutive Androstane Receptor is involved in the sexually dimorphic response to pesticide exposure.<br><div> CONCLUSIONS: We show for the first time the sexually dimorphic obesogen and diabetogen effects of a chronic dietary exposure to a realistic mixture of pesticides, which are partially mediated through CAR. This raises questions about the relevance of ADI for individual pesticides when present in a mixture.</div><div><br></div><div><b>Untargeted urine UPLC-MS assay</b> protocols and data are reported in the current study <b>MTBLS596</b>.</div><div><br><b>Untargeted urine, plasma and liver NMR assay</b> protocols and data associated to this study are reported in <a href=https://www.ebi.ac.uk/metabolights/mtbls602><b>MTBLS602</b></a>.<br></div>

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Exposure to a persistent organic pollutant mixture and sex-specific steatotic liver disease

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