Metabolic Effects of a Chronic Dietary Exposure to a Low-Dose Pesticide Cocktail in Mice: Sexual Dimorphism and Role of the Constitutive Androstane Receptor (Untargeted urine, plasma and liver NMR assay)

ABSTRACT:

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.

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.

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.
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.

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.

Untargeted urine, plasma and liver NMR assay protocols and data are reported in the current study MTBLS602.

Untargeted urine UPLC-MS assay protocols and data associated to this study are reported in MTBLS596.

INSTRUMENT(S): Nuclear Magnetic Resonance (NMR)

SUBMITTER: Sandrine Ellero-Simatos 

PROVIDER: MTBLS602 | MetaboLights | 2018-05-01

REPOSITORIES: MetaboLights