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National Institute of Environmental Health Sciences

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Publication Detail

Title: Key role of soluble epoxide hydrolase in the neurodevelopmental disorders of offspring after maternal immune activation.

Authors: Ma, Min; Ren, Qian; Yang, Jun; Zhang, Kai; Xiong, Zhongwei; Ishima, Tamaki; Pu, Yaoyu; Hwang, Sung Hee; Toyoshima, Manabu; Iwayama, Yoshimi; Hisano, Yasuko; Yoshikawa, Takeo; Hammock, Bruce D; Hashimoto, Kenji

Published In Proc Natl Acad Sci U S A, (2019 04 02)

Abstract: Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.

PubMed ID: 30890645 Exiting the NIEHS site

MeSH Terms: Animals; Epoxide Hydrolases/biosynthesis*; Epoxide Hydrolases/genetics; Female; Gene Expression Regulation, Enzymologic/drug effects*; Maternal Exposure/adverse effects*; Mice; Neurodevelopmental Disorders*/chemically induced; Neurodevelopmental Disorders*/genetics; Neurodevelopmental Disorders*/metabolism; Neurodevelopmental Disorders*/prevention & control; Phenylurea Compounds/pharmacology*; Piperidines/pharmacology*; Prefrontal Cortex*/metabolism; Prefrontal Cortex*/pathology; Pregnancy; Prenatal Exposure Delayed Effects*/chemically induced; Prenatal Exposure Delayed Effects*/genetics; Prenatal Exposure Delayed Effects*/metabolism; Prenatal Exposure Delayed Effects*/prevention & control; Schizophrenia*/chemically induced; Schizophrenia*/genetics; Schizophrenia*/metabolism; Schizophrenia*/prevention & control

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