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·2023
Long-term exposure of bis(2-ethylhexyl) phthalate causes neurobehavioral disorders by disrupting glutamate-glutamine homeostasis in the mPFC
Jae Soon Kang, Ji Hyeong Baek, Mi yeong Song, Hyeong Chan Park, Naveed ur Rehman, Hye Jin Chung, Dong‐Kun Lee, Dae Young Yoo, Hyun Joon Kim
ISEE Conference Abstracts
초록

BACKGROUND AND AIM: Bis(2-ethylhexyl) phthalate (DEHP) is the most used phthalate and its extensive use allows daily exposure to humans via various routes. Although a positive relationship between DEHP exposure and neurobehavioral disorders is suspected, there are insufficient data on the harmfulness of neurobehavioral disorders caused by DEHP exposure, particularly at daily exposure levels. We try to identify the relationship between DEHP and neurobehavioral disorders, and explain the underlying mechanism. METHOD: We assessed the consequences of DEHP ingestion including daily exposure concentration in male mice for 30 (short-term) and 100 (long-term) days and examined its effects on neuronal functions associated with neurobehavioral disorders, such as depression and cognitive decline. RESULTS: We found the noticeable depressive behaviors and decline of learning and memory function in the DEHP-ingestion groups, and that biomarkers related to chronic stress such as corticosterone and ROS/RNS were elevated in plasma and brain tissues. DEHP ingestion induced collapse of glutamate (Glu) and glutamine (Gln) homeostasis as a result of disruption of the Glu-Gln cycle in the medial prefrontal cortex and hippocampus. The electrophysiological approach demonstrated that DEHP ingestion lowered the glutamatergic neurotransmission activity involved in emotional and cognitive functions in the brain. CONCLUSIONS: Our research revealed that the long-term exposure of environment-relevant DEHP, even levels of exposure lower than the tolerable daily intake (TDI), have the strong potential to cause neurobehavioral disorders. Further, since the developing and commercializing a safe substance to replace DEHP is a time-consuming process, it is necessary to prepare stricter regulations and to develop and implement a method to prevent neurobehavioral disorders caused by daily exposure to DEHP to protect the human mental health from this hazardous material. This research was supported by the National Research Foundation (NRF-2020R1I1A1A0107229813, 2021R1A5A802949012, 2022R1A2C100529611 and 2023R1A2C1005658) and the Commercializations Promotion Agency for R&D Outcomes (1711173796) funded by the Korea government.

키워드
GlutaminePhthalateGlutamate receptorHomeostasisChemistryToxicologyMedicineBiochemistryBiologyInternal medicine
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2023