Ducroq Suzanne, Duplus Eric, Grange-Messent Valérie, Francesca Trivelloni, Penalva-Mousset Lucille, Petropoulos Isabelle, Mhaouty-Kodja Sakina
Sorbonne Université, CNRS UMR 8246, INSERM U1130, Neuroscience Paris Seine - Institut de Biologie Paris Seine, 75005, Paris, France.
Sorbonne Université, CNRS UMR 8256, INSERM ERL1164, Biological Adaptation and Ageing - Institut de Biologie Paris-Seine, 75005, Paris, France.
Environ Pollut. 2023 Apr 15;323:121341. doi: 10.1016/j.envpol.2023.121341. Epub 2023 Feb 22.
We recently showed that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture altered blood brain barrier integrity and induced an inflammatory profile in the hippocampus. Here, we investigate whether such exposure alters hippocampus-dependent behavior and underlying cellular mechanisms. Adult C57BL/6 J male mice were continuously exposed orally to the vehicle or DEHP alone (5 or 50 μg/kg/d) or to DEHP (5 μg/kg/d) in a phthalate mixture. In the Morris water maze, males showed reduced latencies across days to find the platform in the cue and spatial reference memory tasks, regardless of their treatment group. In the probe test, DEHP-50 exposed males displayed a higher latency to find the platform quadrant. In the temporal order memory test, males exposed to DEHP alone or in a phthalate mixture were unable to discriminate between the most recently and previously seen objects. They also displayed reduced ability to show a preference for the new object in the novel object recognition test. These behavioral alterations were associated with a lowered dendritic spine density and protein levels of glutamate receptors and postsynaptic markers, and increased protein levels of the presynaptic synaptophysin in the hippocampus. Metabolomic analysis of the hippocampus indicated changes in amino acid levels including reduced tryptophan and L-kynurenine and elevated NAD + levels, respectively, a precursor, intermediate and endproduct of the kynurenine pathway of tryptophan metabolism. Interestingly, the protein amounts of the xenobiotic aryl hydrocarbon receptor, a target of this metabolic pathway, were elevated in the CA1 area. These data indicate that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture impacted hippocampal function and structure, associated with modifications in amino acid metabolites with a potential involvement of the kynurenine pathway of tryptophan metabolism.
我们最近发现，成年雄性小鼠长期暴露于环境剂量的邻苯二甲酸二（2-乙基己基）酯（DEHP）单独或与其他邻苯二甲酸盐混合的环境中，会改变血脑屏障的完整性，并在海马体中引发炎症反应。在此，我们研究这种暴露是否会改变依赖海马体的行为及潜在的细胞机制。成年C57BL/6 J雄性小鼠连续口服溶剂、单独的DEHP（5或50μg/kg/天）或与其他邻苯二甲酸盐混合的DEHP（5μg/kg/天）。在莫里斯水迷宫实验中，无论其所属治疗组如何，雄性小鼠在提示和空间参考记忆任务中找到平台的潜伏期在数天内均缩短。在探针测试中，暴露于50mg/kg DEHP的雄性小鼠找到平台象限的潜伏期更长。在时间顺序记忆测试中，单独暴露于DEHP或与其他邻苯二甲酸盐混合暴露的雄性小鼠无法区分最近和先前看到的物体。在新物体识别测试中，它们对新物体表现出偏好的能力也降低。这些行为改变与海马体中树突棘密度降低、谷氨酸受体和突触后标记物的蛋白质水平降低以及突触前突触素的蛋白质水平升高有关。海马体的代谢组学分析表明，氨基酸水平发生了变化，包括色氨酸和L-犬尿氨酸减少，以及NAD +水平升高，分别是色氨酸代谢犬尿氨酸途径的前体、中间体和终产物。有趣的是，该代谢途径的靶点——外源性芳基烃受体的蛋白质含量在CA1区域升高。这些数据表明，成年雄性小鼠长期暴露于环境剂量的DEHP单独或与其他邻苯二甲酸盐混合，会影响海马体功能和结构，这与氨基酸代谢产物的改变有关，色氨酸代谢的犬尿氨酸途径可能参与其中。
