Dauwe Yannick, Marie Lucile, Grimaldi Marina, Balaguer Patrick, Lippi Yannick, Gayrard Veronique, Mselli-Lakhal Laila
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31027 Toulouse, France.
Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université Montpellier, Institut régional du Cancer de Montpellier (ICM), 34090 Montpellier, France.
Environ Int. 2025 Aug;202:109697. doi: 10.1016/j.envint.2025.109697. Epub 2025 Jul 22.
Pesticides are essential in modern agriculture but raise concerns about long-term metabolic effects, particularly through nuclear receptor activation. This study examines the impact of chronic exposure to a cocktail of five pesticides (dieldrin, propiconazole, boscalid, bupirimate, and pendimethalin) with or without tributyltin (TBT) on glucose and lipid metabolism in mice, focusing on the role of the constitutive androstane receptor (CAR) and pregnane X receptor (PXR). TBT was included for its strong affinity for RXR, a key heterodimerization partner of CAR and PXR, to assess whether RXR activation modulates or amplifies the metabolic effects of pesticide exposure. Results showed that pesticide exposure at NOAEL levels altered CAR and PXR dependent metabolic pathways. CAR knockout mice exhibited reduced free fatty acids and fasting glycemia, while PXR activation led to lower peak glycemia in oral glucose tolerance tests. Transcriptomic analysis identified disrupted pathways linked to glucose uptake and insulin sensitivity. These findings suggest that low-dose pesticide exposure can subtly affect metabolism via nuclear receptor interactions. The inclusion of TBT emphases RXR's role in metabolic regulation. Overall, the study underscores the need to consider cocktail effects in risk assessment.
农药在现代农业中至关重要，但引发了人们对其长期代谢影响的担忧，尤其是通过核受体激活产生的影响。本研究考察了长期暴露于由五种农药（狄氏剂、丙环唑、啶酰菌胺、乙嘧酚和二甲戊灵）组成的混合物中，无论有无三丁基锡（TBT），对小鼠葡萄糖和脂质代谢的影响，重点关注组成型雄甾烷受体（CAR）和孕烷X受体（PXR）的作用。纳入TBT是因为它对RXR具有很强的亲和力，而RXR是CAR和PXR的关键异源二聚体伙伴，以此评估RXR激活是否会调节或放大农药暴露的代谢效应。结果表明，在无可见有害作用水平下的农药暴露改变了CAR和PXR依赖性代谢途径。CAR基因敲除小鼠的游离脂肪酸和空腹血糖降低，而PXR激活导致口服葡萄糖耐量试验中的血糖峰值降低。转录组分析确定了与葡萄糖摄取和胰岛素敏感性相关的紊乱途径。这些发现表明，低剂量农药暴露可通过核受体相互作用微妙地影响代谢。TBT的纳入强调了RXR在代谢调节中的作用。总体而言，该研究强调了在风险评估中考虑混合效应的必要性。
