Epigenetic Regulation DNA Methylation Of Placental Mediates Maternal Cadmium-induced Fetal Growth Restriction In Mouse

Cadmium(Cd)is one of the most toxic environmental pollutants that cause fetal malformation and growth restriction.However,the molecular mechanisms underlying maternal Cd toxicity on fetal growth remain largely unknown.Specifically,the role of placental nutrient transporters,including glucose transporters(GLUTs),has been poorly characterized in the etiology of Cd-induced fetal growth restriction(FGR).In the present study,we established a murine model of FGR induced by maternal Cd exposure,and used Real-time quantitative?West Blots?bisulfite PCR to examine the toxic effects of Cd on placental GLUTs.Our results showed that GLUT3 is significantly downregulated in Cd-exposed mouse placentas when compared to the normal ones.Data from bisulfite PCR demonstrated the hypermethylation of the promoter region of GLUT3.However,methylation levels remained unchanged in two major repetitive elements(LINE-1 and IAP)in Cd-exposed placentas.Moreover,DNA methyltransferase(DNMT)3B and DNMT3 L were significantly upregulated in Cd-exposed placentas,and there were no expression changes of DNMT1 and DNMT3 A.Collectively,the results suggest that:(1)Maternal Cd exposure significantly decreases the fetal weight and placental weight by end of the gestation period.(2)Cadmium accumulation in placenta but not in fetus indicates that the Cd-induced fetal growth restriction relies on the toxic effects of the placentas,rather than on direct toxicity to fetus.(3)Fetal growth restriction in Cd-treated mice correlates with a decrease in GLUT3.The decrease in GLUT3 expression may be caused by site-specific DNA methylation through over-expression of DNMT3 B and DNMT3 L.