Screening for putative epimutagens in neural stem cells derived from human induced pluripotent stem cells

The prevalence of pediatric neurological disorders has increased in recent years and has emerged as a major social concern. While genetic factors play a role, environmental factors may also contribute to these disorders, particularly exposure to harmful chemicals in the fetal environment during pregnancy. However, the concentrations of these chemicals in the fetal environment are extremely low compared with those in experimental conditions, and their influence on the development of neurological disorders after birth remains unclear. Epigenetic regulation plays a crucial role in gene expression and/or chromatin formation, ensuring normal cellular development and differentiation. The relationship between impaired epigenetic regulation and neurological disorders has been previously reported. Therefore, this study aimed to identify chemicals that disrupt epigenetic systems at detectable concentrations in pregnant mothers' serum using a human neural differentiation model. Among the 11 chemicals, including pesticides and heavy metals, exposure to octachlorodipropyl ether (S-421) altered heterochromatin formation in neural stem cells at concentrations found in maternal and umbilical cord blood serum. Additionally, exposure to several chemicals, including S-421, affected neural differentiation, leading to excessive neural fiber growth. Furthermore, S-421 exposure induced DNA hypermethylation of the neural-related genes Cadherin 2 (CDH2) and Sry-related HMG-Box gene 10 (SOX10) in neural stem cells. These findings suggest that S-421, which is present in the fetal environment, functions as an epimutagen that disrupts the epigenetic system within biologically relevant exposure levels. The established epimutagenic screening is expected to provide new insights into the relationship between prenatal chemical exposure and postnatal childhood neurological disorders.