Plasma Folate and Selenium Concentrations and Gene Polymorphisms of Selenoprotein, One Carbon Metabolism Related Enzymes and Arsenic Methylation Related Enzymes and Developmental Delay in Preschool Children

Our previous studies have well documented the poor arsenic metabolism capability was associated with an increased risk of urothelial carcinoma either in arseniasis endemic area or in non-arsenic exposure area. We also found that urinary total arsenic levels were significantly associated with the odds ratio of chronic kidney disease and renal cell carcinoma in a dose-response manner. A recent American study reported that the mental retardation and developmental delays in children was related with the arsenic exposure of mother during pregnancy. Prevalence of developmental delays in 3-5 year-old children increased in Taiwan year by year. Since children with developmental delays require more healthcare services than the general population, the increased prevalence of developmental delays raises an important public health issue. Therefore, it is important to explore the etiology of developmental delay in preschool children. Our recent study showed that urinary total arsenic levels and monomethylarsonic acid (MMAV) percentage were significantly positively associated and dimethylarsinic acid (DMAV) percentage was negatively associated with the risk of developmental delay in a dose-dependent manner after adjustment for blood lead or mercury levels and other risk factors. However, the mechanism of arsenic methylation capacity related developmental delays is still unclear. Therefore, the specific aims of this project are to explore the association among plasma selenium and folate concentrations, and gene polymorphism of selenoprotein (SEPP1 and SEP15), one carbon metabolism related enzymes such as methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) and cystathionine-b-synthase (CBS), and arsenic methylation related enzymes such as arsenic methylatransferase (As3MT), purine nucleoside phosphorylase (PNP) and glutathione-S- transferase omega (GSTO) and developmental delay. In addition, we will explore the interaction of plasma selenium and folate concentration and gene polymorphisms of selenoprotein, one carbon metabolism related enzymes, and arsenic methylation related enzymes on developmental delay after adjustment for plasma lead and mercury levels, and other risk factors. This project is a three-year prospective study. We will use 179 developmental delay preschool children and their mothers and 88 normal developmental preschool children and their mothers recruited previously in our pilot study from Shin Kong Wu Ho-Su Memorial Teaching Hospital. We carried out the questionnaire interviews and collected their bio-specimens including plasma, buffy coat, and urine after they provided their written informed consents. Their urinary arsenic species were determined already. We will continue to recruit 20-30 developmental delay preschool children and their mothers, and 20-30 normal developmental preschool children and their mothers in next three each years. First year the plasma selenium, lead and mercury concentrations and the gene polymorphisms of selenoprotein SEPP1 (rs3797310) and SEP15 (rs5859) will be examined. Second year, we will continue examine plasma selenium, lead and mercury concentrations and gene polymorphisms of selenoprotein of new study subjects and measure plasma folate concentrations and gene polymorphisms of one carbon metabolism related enzymes such as MTHFR (C677T, A1298C, G1793A, rs9651118 and rs1476413), MTR (rs1801394) and CBS (rs234709 and rs4920037) of all study subjects. Third year we will continue to assay plasma selenium, lead, mercury and folate concentrations, and the gene polymorphism of selenoprotein genes and one carbon metabolism related enzymes of new study subjects. We also determine urinary arsenic species of new study subjects and arsenic methylation related enzymes As3MT (rs10748835, rs3740393, rs3740392, rs11191438, rs3740391, rs11191439, rs11191453, rs11191454, rs10748835 and rs1046778), PNP (rs1049562, rs1049564, rs1130650) and GSTO (rs2282326, rs4925, rs11509438, rs2297235 and rs156697) of all study subjects. This study will use external exposure dose, internal dose and susceptibility genes to perform molecular epidemiology of developmental delay in preschool children for examining plasma selenium and folate concentrations and gene polymorphisms of SEPP1, SEP15, MTHFR, MTR, CBS, As3MT, PNP, and GSTO on developmental delay risk in preschool children after adjustment for plasma lead and mercury and other risk factors. Finally, we will incorporate all external exposure dose, internal dose and susceptibility genes to perform statistical analyses. We anticipate setting up and evaluating the interaction of plasma selenium and folate concentrations, gene polymorphisms of selenoprotein gene, one carbon metabolism related enzymes, and arsenic metabolism related enzymes on developmental delay risk in preschool children. We expect to understand a part of mechanisms on developmental delay in preschool children. The findings from these three years projects are expected to publish in internationally prestigious journals.