Effects Of Prenatal Metal Exposure On Physical Development And Non-specific Immune Indexes Of Preschool Children

Background:China’s rapid industrial revolution and urbanization process have increased the pollution of heavy metals to the environment,and the potential impact of heavy metal pollutants on human health has received increasing attention.More and more studies have shown that intrauterine exposure to heavy metal pollutants arsenic（As）,cadmium（Cd）,and lead（Pb）is prone to adversely affect fetal intrauterine development,and may even have a sustained impact on the development of offspring.However,in the past many studies have studied the relationship between single heavy metal exposure and physical development,and the relationship between multiple metal exposure and children’s physical development remains to be elucidated.In addition,intrauterine exposure to heavy metals has been shown to affect the immune function of the offspring.In previous studies,specific immune-related lymphocytes and monocytes were slightly mentioned,but there is a lack of research on non-specific immunity.Based on a large prospective birth cohort,this study detected the concentrations of9 metals in the prenatal urine of 4,410 pregnant women,including vanadium（V）,chromium（Cr）,manganese（Mn）,cobalt（Co）,and nickel（Ni）,Arsenic（As）,cadmium（Cd）,lead（Pb）,thallium（Tl）,to explore the effects of prenatal metal exposure on the physical development and non-specific immune indicators of 3-year-old children.Part 1:The effect of prenatal metal exposure on physical development of preschool childrenObjective:To explore the effect of prenatal metal exposure on physical development of preschool children.Methods:This study is based on a prospective birth cohort.The study population was selected from 4,410 pregnant women and their children who were recruited in Wuhan from September 2012 to April 2015 and provided childbirth urine samples.The concentration of metals in urine before delivery（collected within 3 days before delivery）was used as a marker of intrauterine exposure in children,and 9 kinds of urine samples from pregnant women were measured by inductively coupled plasma mass spectrometry（ICP-MS）The concentration of metal,and the determination of urine creatinine concentration at the same time,is used to correct the concentration of urine metal.Collect the height and weight of children at the age of 3,and calculate the body mass index（BMI）.Based on the child growth and development standards issued by the World Health Organization（WHO）in 2006,the physical indicators of the 3-year-old children are Months of age were corrected for weight-Zscore,height-Zscore,and BMI-Zscore.Because the concentration of various metals in the mother’s urine before delivery was left-skewed,the natural logarithm conversion of the metal concentration was included in the model.A generalized linear regression model was used to analyze the association between prenatal single-metal exposure and 3-year-old children’s standardized physical development indicators,and stratified analysis according to children’s gender.The metal exposure and gender interaction terms were used to determine whether the effect of metal on children’s physical development was gender.difference.And further analyze the relationship between multi-metal exposure and children’s physical development.Results:The detection rate of 9 metals is more than 94%,of which 100%is detected for cobalt（Co）,arsenic（As）and cadmium（Cd）.The median values of urinary creatinine corrected for urinary creatinine were arsenic（As）:28.50,nickel（Ni）:4.93,lead（Pb）:3.44,chromium（Cr）:1.89,manganese（Mn）:1.59 Vanadium（V）:1.41,Cobalt（Co）:1.40,Cadmium（Cd）:0.58,Thallium（Tl）:0.53μg/g.The prenatal urine metal levels of this study population were higher than those of pregnant women in developed countries such as Australia and the United States;but lower than those of pregnant women in metal-contaminated areas such as Myanmar,Bangladesh,and Guiyu,China..After adjusting for possible confounding factors and adjusting the P value in the model by FDR,the single-metal exposure model found a positive correlation between prenatal cobalt（Co）and child height-Zscore(%change=6.00%,95%CI:2.43%,9.57%,P_-FDR=0.01),after sex stratification,it is still positively correlated among girls(%change=7.28%,95%CI:2.46%,12.10%,P_-FDR=0.03),but there is no statistical relationship among boys Academic significance(P_-FDR=0.55);Thallium（Tl）found positive correlation with girls BMI-Zscore（%change=8.68%,95%CI:3.00%,14.35%,P-FDR=0.02）,but there was no statistical significance among boys(P_-FDR=0.85).The results of the multi-metal exposure model and the single-metal exposure model are basically the same.Cobalt（Co）is positively correlated with the child height-Zscore(%change=5.68%,95%CI:1.69%,9.67%,P_-FDR=0.04);It was positively correlated with girls’BMI-Zscore(%change=9.81%,95%CI:3.00%,16.62%,P_-FDR=0.04),but there was no statistical significance among boys(P_-FDR=0.63).P_-interaction of gender differences was not statistically significant.Conclusion:Pregnant women in Wuhan are widely exposed to various metals,with the highest concentration of arsenic（As）and the lowest concentration of thallium（Tl）.Prenatal urine metal levels are higher than pregnant women in developed countries such as Australia and the United States,but lower than those in metal-contaminated areas such as Myanmar,Bangladesh,and Guiyu,China.No particularly strong relationship was found between prenatal metal exposure and the physical fitness of 3-year-old children.Prenatal exposure to cobalt（Co）may be positively correlated with the height of 3-year-old children;prenatal exposure to thallium（Tl）may be positively correlated with girl BMI.The influence of prenatal metals on the growth and development of children needs further research on the influence of postnatal growth trajectories.Part 2:The effect of prenatal metal exposure on non-specific immune indicators of preschool childrenObjective:To explore the effect of prenatal metal exposure on non-specific immune indexes of preschool children.Methods:This study is based on a prospective birth cohort.601 pregnant women who were recruited in Wuhan from October 2013 to April 2016 and provided childbirth urine samples（collected 3 days before childbirth）and their children had a medical record at 3 years of age 601 For mother and baby.Using automatic biochemical instrument to detect various types of venous blood leukocyte counts during physical examination in children.A generalized linear regression model was used to analyze the association between single-metal exposure in utero and non-specific immunity levels of preschool children,and stratified analysis according to children’s gender.The metal×gender interaction term was used to determine whether the effect of heavy metals on innate immune cells had gender differences.In addition,the metal concentration is stratified according to quartiles,with the lowest quartile as the reference group,the metal is included in the model as a categorical variable,and the above analysis is repeated,and the median value of each group is re-assigned,and the re-assigned variable is continuous The form of sexual variables is included in the model,and the trend Ptrend is calculated to clarify the dose-response relationship.A false discovery rate（FDR）is used to control the false positive rate generated by multiple hypothesis testing.Results:In the model of metal as a continuous variable,after adjusting for confounding factors,for every natural log unit of intrauterine cadmium（Cd）exposure,the lymphocyte count（LYMPH）of children decreased by 14.00%(95%CI:-22.38%,-5.74%,P_-FDR=0.01).After sex stratification,for every natural log unit increase in intrauterine cobalt（Co）exposure,the boy’s lymphocyte count（LYMPH）decreased by14.85%(95%CI:-24.14%,-4.25%,P_-FDR=0.05),This negative correlation was not statistically significant in girls(P_-FDR=0.33),and there was no statistically significant difference in gender（P-interaction=0.78）;for each additional natural log unit of intrauterine cadmium（Cd）exposure,boys’lymph The cell count（LYMPH）decreased by15.32%(95%CI:-25.87%,-3.77%,P_-FDR=0.05),this negative association was not statistically significant among girls(P_-FDR=0.91),and the gender difference was not Statistical significance(P_-interaction=0.78);for each additional natural logarithmic unit of intrauterine vanadium（V）exposure,the boy’s eosinophil count（EOS）and eosinophil percentage（EOS%）decreased by 23.05%(95%CI:-35.9%,-7.61%,P_-FDR=0.05),19.71%(95%CI:-30.63%,-7.07%,P_-FDR=0.03),no statistically significant association among girls(P_-FDR=0.64,0.45),gender interaction P_-interaction=0.072,0.027.In the model with metal as a categorical variable,the fourth group of manganese（Mn）had a reduction in eosinophils（EOS%）of 21.75%(95%CI:-32.29%,-9.55%,P_-FDR=0.01),the third group and the second group are not statistically significant compared with the first group,but the linear trend is significant(P_-trend=0.009),and the exposure levels of other metals are not statistically related to each white blood cell count.Under mixed multi-metal exposure,for every natural log unit increase in intrauterine manganese（Mn）exposure,boy white blood cell count（WBC）increased by 7.08%(95%CI:2.35%,12.03%,P_-FDR=0.03),among girls No statistically significant association(P_-FDR=1.00);the percentage of girls’monocytes（MONO%）decreased with the increase in manganese（Mn）exposure by 9.47%(95%CI:-14.91%,-3.68%,P_-FDR=0.02),and this association was not statistically significant in boys(P_-FDR=0.87),and there was no gender difference in the above associations(P_-interaction>0.05).Conclusion:At current environmental exposure levels,intrauterine exposure to vanadium（V）,cobalt（Co）,and cadmium（Cd）may be associated with a decrease in the white blood cell count of preschool-age 3-year-old boys.),Cobalt（Co）and cadmium（Cd）are negatively correlated with lymphocyte count（LYMPH）.There is a gender difference in the association between vanadium（V）and the percentage of eosinophils（EOS%）.High levels of manganese（Mn）in utero may be related to a decrease in the percentage of eosinophils（EOS%）in preschool-age 3-year-old children.Under mixed metal exposure,intrauterine manganese（Mn）may be associated with an increase in white blood cell count（WBC）in boys and a decrease in the percentage of mononuclear cells（MONO%）in girls.These results indicate that intrauterine exposure to vanadium（V）,cobalt（Co）,cadmium（Cd）,and manganese（Mn）may have an impact on the non-specific immune levels of preschool children,especially immunosuppression.