Institute of Functional Genomics, University of Montpellier, CNRS, INSERM, Montpellier, France.
Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France.
Environ Pollut. 2024 Mar 15;345:123477. doi: 10.1016/j.envpol.2024.123477. Epub 2024 Jan 31.
Prolonged exposure to low levels of dietary contaminants is a context in modern life that could alter organ physiology gradually. Here, we aimed to investigate the impact of continuous exposure to acceptable daily intake (ADI) and non-observable adverse effect level (NOAEL) of glyphosate from gestation to adulthood using C57BL/6J mice and incorporating these levels into their food pellets. From adulthood, we analyzed neurophysiological and neuro-glia cellular adaptations in male and female animals. Using ex-vivo hippocampal slice electrophysiology, we found a reduced efficacy of Schaffer collateral-to-CA1 excitatory synapses in glyphosate-exposed dietary conditions, with ADI and NOAEL dose-dependent effects. Short-term facilitation of excitatory synaptic transmission was specifically increased in NOAEL conditions, with a predominant influence in males, suggesting a reduced probability of neurotransmitter release. Long-term synaptic potentiation (LTP) was decreased in NOAEL-exposed mice. Next, we explore whether these neurophysiological modifications are associated with neuro-glia changes in the somatosensory cortex and hippocampus. High-resolution confocal microscopy analyses unveil a dose-dependent increased density of excitatory Vglut1 Homer1 synapses. Microglial Iba1 cells displayed a shortening of their ramifications, a sign of cellular reactivity that was more pronounced in males at NOAEL levels. The morphology of GFAP astrocytes was generally not modified. Finally, we asked whether mouse-specific cross-correlations exist among all data sets generated. This examination included the novel object recognition (NOR) test performed before ex vivo functional and immunohistochemical examinations. We report a negative linear regression between the number of synapses and NOR or LTP maintenance when plotting ADI and NOAEL datasets. These results outline synaptic and microglial cell adaptations resulting from prenatal and continuous dietary low levels of glyphosate, discernible in, but not limited to, adult males exposed to the NOAEL. We discuss the potential significance of these findings to real-world consumer situations and long-term brain resilience.
长期暴露于低水平的饮食污染物是现代生活中的一种情况，可能会逐渐改变器官的生理机能。在这里，我们旨在研究连续暴露于妊娠期至成年期的 glyphosate 的可接受日摄入量 (ADI) 和未观察到不良作用水平 (NOAEL) 对 C57BL/6J 小鼠的影响，并将这些水平纳入其食物颗粒中。从成年期开始，我们分析了雄性和雌性动物的神经生理和神经胶质细胞适应性。通过离体海马切片电生理学，我们发现暴露于 glyphosate 的饮食条件下，Schaffer 侧枝到 CA1 兴奋性突触的效力降低，ADI 和 NOAEL 剂量依赖性效应。兴奋性突触传递的短期易化在 NOAEL 条件下特异性增加，雄性中占主导地位，表明神经递质释放的可能性降低。NOAEL 暴露的小鼠中的长时程突触增强 (LTP) 降低。接下来，我们探讨这些神经生理变化是否与感觉皮层和海马中的神经胶质变化有关。高分辨率共聚焦显微镜分析揭示了兴奋性 Vglut1 Homer1 突触的密度呈剂量依赖性增加。小胶质细胞 Iba1 细胞的分支缩短，这是细胞反应性的标志，在 NOAEL 水平下雄性更为明显。GFAP 星形胶质细胞的形态通常没有改变。最后，我们询问在生成的所有数据集之间是否存在特定于小鼠的交叉相关性。这项检查包括在离体功能和免疫组织化学检查之前进行的新物体识别 (NOR) 测试。当绘制 ADI 和 NOAEL 数据集时，我们报告了突触数量与 NOR 或 LTP 维持之间的负线性回归。这些结果概述了产前和连续低水平 glyphosate 饮食引起的突触和小胶质细胞适应性，这些适应性在暴露于 NOAEL 的成年雄性中可见，但不限于成年雄性。我们讨论了这些发现对现实世界消费者情况和长期大脑弹性的潜在意义。
