Inulin Supplementation Lowered the Metabolic Defects of Prolonged Exposure to Chlorpyrifos from Gestation to Young Adult Stage in Offspring Rats

Increasing evidence indicates that chlorpyrifos (CPF), an organophosphorus insecticide, is involved in metabolic disorders. We assess the hypothesis whether supplementation with prebiotics from gestation to adulthood, through a modulation of microbiota composition and fermentative activity, alleviates CPF induced metabolic disorders of 60 days old offspring. 5 groups of Wistar rats, from gestation until weaning, received two doses of CPF pesticide: 1 mg/kg/day (CPF1) or 3.5 mg/kg/day (CPF3.5) with free access to inulin (10g/L in drinking water). Then male pups received the same treatment as dams. Metabolic profile, leptin sensitivity, insulin receptor (IR) expression in liver, gut microbiota composition and short chain fatty acid composition (SCFAs) in the colon, were analyzed at postnatal day 60 in the offspring (PND 60). CPF3.5 increased offspring’s birth body weight (BW) but decreased BW at PND60. Inulin supplementation restored the BW at PND 60 to control levels. Hyperinsulinemia and decrease in insulin receptor β in liver were seen in CPF1 exposed rats. In contrast, hyperglycemia and decrease in insulin level were found in CPF3.5 rats. Inulin restored the levels of some metabolic parameters in CPF groups to ranges comparable with the controls. The total bacterial population, short chain fatty acid (SCFA) production and butyrate levels were enhanced in CPF groups receiving inulin. Our data indicate that developmental exposure to CPF interferes with metabolism with dose related effects evident at adulthood. By modulating microbiota population and fermentative activity, inulin corrected adult metabolic disorders of rats exposed to CPF during development. Prebiotics supply may be thus considered as a novel nutritional strategy to counteract insulin resistance and diabetes induced by a continuous pesticide exposure.

越来越多的证据表明，有机磷杀虫剂毒死蜱（chlorpyrifos, CPF）可参与代谢紊乱的发生过程。本研究旨在验证下述假说：从妊娠期至成年期补充益生元（prebiotics），通过调控微生物群组成与发酵活性，能否缓解60日龄子代大鼠由毒死蜱诱导的代谢紊乱。本研究设置5组Wistar大鼠（Wistar rats），从妊娠期至断奶期对其施加两种剂量的毒死蜱：分别为1 mg/kg/天（CPF1组）与3.5 mg/kg/天（CPF3.5组），各组可自由饮用添加了10g/L菊糖（inulin）的饮水。随后，雄性幼崽接受与母鼠相同的处理方案。于仔鼠出生后第60天（postnatal day 60, PND 60），检测其代谢谱（metabolic profile）、瘦素敏感性（leptin sensitivity）、肝脏胰岛素受体（insulin receptor, IR）表达水平、肠道微生物群组成以及结肠短链脂肪酸（short chain fatty acid, SCFAs）组成。结果显示，CPF3.5组可升高仔鼠的出生体重（body weight, BW），但会降低其在PND60时的体重；补充菊糖可将PND60时的仔鼠体重恢复至对照组水平。CPF1暴露组大鼠可见高胰岛素血症，以及肝脏胰岛素受体β亚基表达水平下调。与之相反，CPF3.5组大鼠则出现高血糖症与胰岛素水平下调。补充菊糖可将CPF处理组的部分代谢参数恢复至与对照组相当的水平。在补充菊糖的CPF处理组中，总细菌数量、短链脂肪酸（SCFA）生成量以及丁酸（butyrate）水平均得到提升。本研究数据表明，发育期暴露于毒死蜱会干扰机体代谢，且其剂量相关效应在成年期可被观测到。通过调控微生物群组成与发酵活性，菊糖可改善发育期暴露于毒死蜱的大鼠在成年期出现的代谢紊乱。因此，补充益生元可被视为一种新型营养策略，用于对抗持续农药暴露所诱导的胰岛素抵抗与糖尿病。