In Utero Exposure to Lead is Associated with Neural Tube Defects via Disturbing the Expression of Endocannabinoid Retrograde Signaling-Related Genes

Neural tube defects (NTDs) are a group of severe congenital malformations of the central nervous system, for which environmental causes are not fully known. In a human case–control study, we compared lead (Pb) levels in umbilical cord blood serum from 40 NTD cases and 119 controls. In a toxicology study, we treated Institute of Cancer Research (ICR) mice with different dosage of Pb acetate orally from gestational day (GD) 6.5 through 9.5. At GD10.5, mouse embryos were harvested and examined. RNA-sequencing was conducted on the embryos to detect mRNA profiles. siRNAs were used to pull down target genes in human embryonic stem cells to examine the effects of the aberrant gene expression on neural cells. A higher Pb concentration in cord serum was associated with the odds of NTDs [odds ratio (OR): 4.66 (1.69–15.24)]. Lead acetate induced NTDs in 10.6% of mouse fetuses. RNA expression profiles of Pb-induced NTD mice were different from control embryos, especially in endocannabinoid retrograde signaling genes Plcb2 , Nfix , and Gabrg2. Down-regulation of Plcb2 and Nfix influenced neural cell differentiation and impaired the formation of neural rosette-like structures. Together, in utero-Pb exposure is associated with development of NTDs via regulating the expression of endocannabinoid retrograde-signaling genes.