| BackgroundArsenic and cadmium are human carcinogens, lead is possibly human carcinogen. A large number of data shows that, arsenic, cadmium, lead can fully or partially through the placental barrier into the fetus, to influence fetal growth and health after birth. Even low exposure may affect fetal growth and development, lead to low birth weight and other hazards.DNA methylation is a very important way of natural chemical modification for mammal. It can regulate the expression of genes, and negatively correlated with gene expression, DNA methylation in the promoter region is positively correlated with transcriptional activity. The changes of DNA methylation state can lead to abnormal gene expression related to cell proliferation and differentiation, this is a key factor in carcinogenesis, it can lead to cells lose the control of normal process then form tumors.There is a little data about intrauterine environment exposure and DNA methylation. Researches show that, urine arsenic of mother is negatively correlation with genome-wide DNA methylation level of cord blood, bone lead of mother is negatively correlation with genome-wide DNA methylation level of cord blood, but these failed to observe the effect of arsenic and lead of cord blood on genome-wide DNA methylation level. Research also shows environmental cadmium exposure can change the level of women’s genome-wide DNA methylation. There is no research about intrauterine cadmium exposure and genome-wide DNA methylation.IGF2and H19gene is a pair of imprinted gene, IGF2only express the paternal alleles (matrilineal imprinted), and H19only express matrilineal allele (paternal imprinted). H19and IGF2have the similar gene location, sharing the same regulation system, play an important role on fetal and postnatal growth and development. Researches show that the methylation level changes of IGF2and H19DMRS can change the expression level of IGF2gene. The expression level of IGF2gene is positively correlation with the growth and development of fetus. Intrauterine famine, cigarette smoke exposure can change the level of IGF2gene methylation in cord blood, and the gene methylation is associated with low birth weight. There is no research on the relationship of intrauterine arsenic, cadmium, lead exposure and IGF2and H19DNA methylation.Based on the above research results, in this topic epidemiological investigation and biological surveillance were used to explore the effect of intrauterine arsenic, cadmium, lead exposure on infant growth and development and its relationship with DNA methylation, look for the possible mechanism of heavy metal affect fetal development, and provide early damage proof for the carcinogenesis of heavy metals.ObjectivesEpidemiological investigation and biological surveillance were used to know the cadmium, arsenic, lead concentration of pregnant and fetus in a city of Hubei Province and its influencing factors;To explore the relationship between metallothionein gene polymorphism and arsenic, cadmium, lead level of blood;To study the effect of intrauterine arsenic, cadmium, lead exposure on the newborn growth;To research the influence of intrauterine arsenic, cadmium, lead exposure on the newborn DNA methylation level and analyze its relationship with the growth and development.Methods 1Epidemiology investigationsField study was conducted in a city of Hubei province. A detailed, validated questionnaire administered to the mother within2days Postpartum included information on the demography, smoking and drinking, residential and environmental exposures, disease and Pregnant history, newborn development indexes.2Sampling and measuringMaternal urine were collected for measuring the arsenic, cadmium, lead concentration by ICP/MS.Maternal blood were collected withinlday postpartum, and umbilical cord blood were collected at delivery to measure the arsenic, cadmium, lead concentration by ICP/MS.Genomic DNA were extracted from maternal blood and cord blood to detect the genotyping of MT1A-rs11076161, MT2A-rs10636and MT2A-rs28366003.The cord blood genomic DNA were used to measure the genome-wide DNA methylation level by LC/MS/MS, observe the IGF2/H19gene methylation level by Pyrophosphate sequencing method.ResμltsPart One Arsenic, cadmium, lead exposure and the related factors1In this study, the median of arsenic, cadmium, lead concentration in mother blood are10.10μg/L,0.70μg/L,34.59μg/L; the median of arsenic, cadmium, lead concentration in mother urine are6.14μg/L,0.33μg/L,5.31μg/L; the median of arsenic, cadmium, lead concentration in cord blood are7.43μg/L,0.16μg/L,26.75μg/L. The arsenic, cadmium, lead concentration in mother blood are higher than in urine. Arsenic, cadmium, lead concentration in mother blood are higher than cord blood.2A significant positive correlation was shown between maternal blood and urine cadmium concentration, so does lead concentration; arsenic, lead concentration of maternal blood are positive associated with cord blood.3Mother’s degree of education, family income, whether living around roads, weight gain during pregnancy, whether taking supplements can affect the blood arsenic levels; mother’s degree of education, family income, weight gain during pregnancy, cooking methods, whether taking supplements can affect the blood cadmium levels; mother’s degree of education, family income will affect the blood lead level.Part Two Maternal and newborn metallothionein gene polymorphism distribution and its relationship with exposure1The arsenic, cadmium, lead concentration of mothers carrying mutation type gene are higher than who carrying wild type gene of MT1A-rs11076161, MT2A MTrs10636, MTrs28366003locus.2The arsenic, cadmium, lead concentration of newborn carrying mutation type gene are higher than who carrying wild type gene of MT1A-rs11076161, MT2A MTrs10636, MTrs28366003locus.Part Three The effect of intrauterine arsenic, cadmium, lead exposure on newborn growth and development1Umbilical cord blood arsenic levels can affect the length, weight, chest circumference of newborn; umbilical cord blood cadmium level can affect the length, chest circumference of newborn; umbilical cord blood lead level affects the length and head circumference of newborn.2Multiple linear stepwise regression analysis found that, cord blood arsenic levels can affect neonatal birth length and chest circumference; umbilical cord blood lead level can affects newborn birth length and head circumference. Every1μg/L increased of umbilical cord blood arsenic lead to0.083cm decrease of neonatal length and neonatal chest circumference reduce0.099cm. Every1μg/L increased of umbilical cord blood lead can lead to0.083cm decrease of neonatal length, and the newborn head circumference reduce0.016cm.Part Four Arsenic, cadmium, lead exposure and DNA methylation1Neonatal genome-wide DNA methylation level of blood arsenic high dose group is higher than the low dose group.2Neonatal IGF2gene methylation level of blood arsenic high dose group is lower than the low dose group; neonatal IGF2gene methylation level of blood cadmium high dose group is higher than the low dose group.3Multiple linear stepwise regression analysis found that, cord blood arsenic levels is positive correlation with genome-wide DNA methylation level; cord blood cadmium levels is negative correlation with genome-wide DNA methylation level; cord blood arsenic levels is negative correlation with IGF2/H19DNA methylation level.Part Five The relationship between neonatal umbilical cord blood DNA methylation and growth and development1Neonatal umbilical cord blood IGF2gene methylation level is negative correlation with birth body length.2There is no correlation between neonatal H19methylation level and growth and development.Conclusion1The blood arsenic and lead of research objects are at a higher exposure levels; the cadmium, lead levels in mother blood are positive correlation with urine, the arsenic, lead levels in mother blood are positive correlation with cord blood.2Metallothionein gene polymorphism can affect the arsenic, cadmium, lead concentration in the blood.3Intrauterine arsenic and lead exposure can affect the growth and development of the newborn.4Intrauterine arsenic, cadmium, exposure can affects newborn genome-wide DNA methylation level.5Intrauterine arsenic exposure can affect the neonatal IGF2/H19gene methylation level.6Neonatal umbilical cord blood IGF2gene methylation level is negative correlation with birth body length. |
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