Kiknadze Natalia, Zhuravliova Elene, Mikeladze David
Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili av., Tbilisi, 0160, Georgia.
Cell Mol Biol (Noisy-le-grand). 2025 Feb 20;71(2):85-94. doi: 10.14715/cmb/2025.71.2.13.
Widespread human exposure to phthalates is caused by their intensive usage in industrial and consumer plastic products. DEHP (di(2-ethylhexyl) phthalate) is one of the most often used phthalates and is presented not only in food and fluids but also in the air and dust contact with plastic products. Regrettably, phthalates easily migrate into the human body and act as potent toxicants, mainly on endocrine and metabolic status. In the last decade, several epidemiological studies have indicated a correlation between prenatal exposure to phthalates and adverse effects on neurodevelopment in offspring. Our research aimed to assess the impact of DEHP prenatal subchronic exposure on male offspring's behavior and learning ability and identify the primary target brain structure/s of neurotoxic action. Heightened anxiety in male offspring was evident through increased rearing, frequent line crossings, hurried movements, and reduced grooming behavior. These behaviors were accompanied by a decline in recognition memory and diminished interest in exploring novel objects. Obtained data showed that prenatal oral exposure to DEHP in a selected concentration induces irreversible changes in brain structures of the male offspring, primarily in the hippocampus, that underlies significant alterations in cognitive behavior and enhanced anxiety. The molecular mechanism of DEHP-induced hippocampal neurotoxicity in the maturing male brain involves changes in phosphatase and tensin homolog (PTEN) subcellular location, which suppresses Akt/mTOR signaling, enhances GluN2B NMDA mediated synapse depression and decreases mitochondrial fusion.
邻苯二甲酸盐在工业和消费塑料制品中的大量使用导致人类广泛接触此类物质。邻苯二甲酸二（2-乙基己基）酯（DEHP）是最常用的邻苯二甲酸盐之一，不仅存在于食品和液体中，还存在于与塑料制品接触的空气和灰尘中。遗憾的是，邻苯二甲酸盐很容易迁移到人体中，并作为强效毒物发挥作用，主要影响内分泌和代谢状态。在过去十年中，多项流行病学研究表明，产前接触邻苯二甲酸盐与后代神经发育的不良影响之间存在关联。我们的研究旨在评估产前亚慢性接触DEHP对雄性后代行为和学习能力的影响，并确定神经毒性作用的主要靶脑结构。雄性后代的焦虑加剧表现为竖毛增加、频繁穿过直线、动作急促以及梳理行为减少。这些行为伴随着识别记忆的下降和对探索新物体兴趣的降低。获得的数据表明，产前经口接触选定浓度的DEHP会导致雄性后代脑结构发生不可逆变化，主要是在海马体，这是认知行为显著改变和焦虑加剧的基础。在成熟雄性大脑中，DEHP诱导海马体神经毒性的分子机制涉及磷酸酶和张力蛋白同源物（PTEN）亚细胞定位的变化，这会抑制Akt/mTOR信号传导，增强GluN2B N-甲基-D-天冬氨酸介导的突触抑制，并减少线粒体融合。
