Maternal Glyphosate Exposure Causes Autism‐like Behaviors in Offspring through Increased Expression of Soluble Epoxide Hydrolase

Abstract

The number of children with autism spectrum disorder (ASD) has increased dramatically since the 1980s. Epidemiological studies suggest that exposure to pesticides (i.e., glyphosate) during pregnancy might increase the risk for ASD in offspring. Recently, we demonstrated that soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids plays a key role in the development of ASD in offspring after maternal immune activation. In the present study, we found ASD‐like behavioral abnormalities in juvenile offspring after maternal glyphosate exposure. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure. Oxylipin analysis showed decreased levels of epoxy‐fatty acids (i.e., 8(9)‐EpETrE [8,9‐epoxy‐5Z,11Z,14Z‐eicosatrienoic acid] in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in juvenile offspring. The 16S rRNA analysis demonstrated abnormal composition of gut microbiota in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU to pregnant mothers from E5 to P21 could prevent social interaction deficits, increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal glyphosate exposure causes ASD‐like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH plays a key role in ASD‐like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH would represent a promising prophylactic target for ASD in offspring after maternal glyphosate exposure.Support or Funding InformationThis study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (to K.H., 17H04243), AMED (to K.H., JP19dm0107119), the National Institute of Environmental Health Sciences (NIEHS) R01 ES002710 (to B.D.H.), NIEHS Superfund Program P42 ES004699 (to B.D.H.).