MetaboLights MTBLS596 - GNPS 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 UPLC-MS assay).

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 UPLC-MS assay protocols and data are reported in the current study MTBLS596.
Untargeted urine, plasma and liver NMR assay protocols and data associated to this study are reported in MTBLS602.

背景：流行病学证据表明，农药暴露与代谢性疾病的发生存在关联。然而，绝大多数实验研究仅针对单一农药分子评估其代谢效应，且多采用非现实暴露剂量，或联合高脂膳食等其他风险因素开展研究。
研究目的：本研究以小鼠为实验模型，旨在评估长期膳食暴露于剂量为无毒且符合消费者风险评估要求的复合农药所产生的代谢效应。
方法：将法国常用的6种农药——啶酰菌胺(boscalid)、克菌丹(captan)、毒死蜱(chlorpyrifos)、硫菌灵(thiofanate)、噻虫啉(thiacloprid)和福美双(ziram)——掺入标准维持饲料中，使小鼠摄入对应每种农药每日允许摄入量(acceptable daily intake, ADI)的剂量。实验对象为野生型(Wild-type, WT)及组成型雄烷受体(Constitutive Androstane Receptor, CAR)敲除(CAR-/-)的C57Bl6/J品系雌雄小鼠，暴露时长为52周。实验期间全程监测代谢相关参数：体重、摄食量与饮水量、葡萄糖耐量及尿液代谢组。实验结束后，采用液相色谱-质谱联用(Liquid Chromatography-Mass Spectrometry, LC/MS)技术分析肝脏代谢（组织学、转录组学、代谢组学）及农药解毒状态。
结果：雄性小鼠经农药暴露后，体重与体脂量升高，诱发肝脂肪变性及葡萄糖耐量异常。暴露后的雌性小鼠出现空腹高血糖、肝脏氧化应激及肠道菌群相关尿液代谢物紊乱。组成型雄烷受体(CAR)参与介导了农药暴露后的性别二态性应答。
结论：本研究首次证实，长期膳食暴露于符合现实暴露场景的复合农药，可产生具有性别二态性的致肥胖及致糖尿病效应，该效应部分由组成型雄烷受体(CAR)介导。这一结果对单一农药每日允许摄入量(ADI)标准在复合暴露场景下的适用性提出了质疑。
本研究的非靶向尿液超高效液相色谱-质谱(Ultra Performance Liquid Chromatography-Mass Spectrometry, UPLC-MS)分析方案及数据已收录于MTBLS596。本研究相关的非靶向尿液、血浆及肝脏核磁共振(Nuclear Magnetic Resonance, NMR)分析方案与数据已收录于MTBLS602。