Maternal di-(2-ethylhexyl) phthalate exposure inhibits cerebellar granule precursor cell proliferation via down-regulating the Shh signaling pathway in male offspring

Abstract Di-(2-ethylhexyl) phthalate (DEHP) is an endocrine disrupting chemical (EDC) widely used as a plasticizer in many materials. Epidemiological investigations have shown that DEHP exposure during early development is related to cerebellar-related adverse neurodevelopmental outcomes. However, animal studies involving the effect of DEHP exposure on cerebellar development have rarely been reported and the potential mechanisms are unclear. The aim of this study was to investigate the effect of maternal DEHP exposure on the proliferation of cerebellar granule cell precursor cells (GCPs) and the mechanisms involved. Wistar rats were randomly assigned to four exposure groups and given 0, 30, 300, or 750 mg/kg/d DEHP by intragastric administration from gestational day (GD) 0 to postnatal day (PN) 21. Exposure to 300 and 750 mg/kg/d DEHP restrained GCPs proliferation and impaired neurodevelopment for males. Furthermore, exposure to 300 and 750 mg/kg/d DEHP decreased male pups protein expressions and mRNA levels of molecules related to proliferation, including Shh, Gli1, N-Myc, CyclinD1. In addition, the estrogen level and aromatase expression also reduced in male pups after maternal exposure to DEHP. However, effects on females were not obvious. These results suggested that 300 and 750 mg/kg/d DEHP exposure inhibit the proliferation of GCPs in male offspring and ultimately contribute to the impairment of neuromotor development. This, may be caused by the down-regulation of Shh signaling. And the susceptibility of male offspring to DEHP exposure may be attributed to the decreased estrogen level and aromatase expression in male pup's cerebellum.