Klement Wendy, Oliviero Fabiana, Gangarossa Giuseppe, Zub Emma, De Bock Frederic, Forner-Piquer Isabel, Blaquiere Marine, Lasserre Frederic, Pascussi Jean-Marc, Maurice Tangui, Audinat Etienne, Ellero-Simatos Sandrine, Gamet-Payrastre Laurence, Mselli-Lakhal Laila, Marchi Nicola
Institute of Functional Genomics (UMR 5203 CNRS - U 1191 INSERM, University of Montpellier), Montpellier, France.
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, 31300 Toulouse, France.
Neuroscience. 2020 Oct 15;446:225-237. doi: 10.1016/j.neuroscience.2020.07.039. Epub 2020 Jul 28.
Exposure to environmental contaminants is a public health concern. However, pre-clinical studies that examine the impact of pesticides at low-dose and the long-term consequences are uncommon. Here, C57BL6/j male and female mice were daily fed from weaning and up to 12 months, corresponding to early-childhood into middle-age in humans, using chow pellets containing a cocktail of pesticides at tolerable daily intake levels. We found that 12 months of dietary exposure to pesticides was associated with a moderate perenchymal or perivascular astrogliosis in specific hippocampal sub-regions. The expression of platelet-derived growth factor receptor beta was modified at the perivascular level. Examination of Iba1 microglial cells did not reveal sizeable changes. Concomitantly to astrogliosis, spontaneous spatial memory and sociability were modified in males at 12 months of dietary exposure to pesticides. Telemetry electrocorticograhic explorations ruled out the presence of epileptiform activity or theta-gamma wave modifications in these conditions. Long-term pesticides impacted the periphery where the hepatic P450 metabolic cytochromes Cyp4a14 and Cyp4a10 were significantly upregulated in male and female mice during the 12 months of exposure. The expression of β-oxidation genes, such as Acox1, Cpt1a and Eci, was also significantly increased in male and female mice in response to pesticides. Collectively, our results indicate that a life-long exposure to a pesticide cocktail elicits sex-dependent, spatio-temporally restricted brain modifications and significant activation of P450 pathways in the periphery. These brain-peripheral adjustments are discussed as time or age-dependent vulnerability elements.
接触环境污染物是一个公共卫生问题。然而，研究低剂量农药影响及其长期后果的临床前研究并不常见。在此，从断奶开始直至12个月大（相当于人类从幼儿期到中年期），每天给C57BL6/j雄性和雌性小鼠喂食含有可耐受每日摄入量水平的农药混合物的饲料颗粒。我们发现，12个月的农药饮食暴露与特定海马亚区中度的实质或血管周围星形胶质细胞增生有关。血小板衍生生长因子受体β的表达在血管周围水平发生了改变。对Iba1小胶质细胞的检查未发现明显变化。与星形胶质细胞增生同时出现的是，在接触农药12个月的雄性小鼠中，自发空间记忆和社交能力发生了改变。遥测脑电图探索排除了在这些情况下存在癫痫样活动或θ-γ波改变。长期接触农药影响了外周，在暴露的12个月期间，雄性和雌性小鼠肝脏中的P450代谢细胞色素Cyp4a14和Cyp4a10显著上调。响应农药，雄性和雌性小鼠中β-氧化基因（如Acox1、Cpt1a和Eci）的表达也显著增加。总体而言，我们的结果表明，终生接触农药混合物会引发性别依赖性、时空受限的大脑改变以及外周P450途径的显著激活。这些大脑-外周的调整被视为与时间或年龄相关的脆弱性因素进行讨论。
