Prenatal Arsenic And Manganese Exposure And Sub-threshold Autistic Traits In Toddlers:A Prospective Birth Cohort Study

ObjectivesEvaluating the exposure levels of serum arsenic and manganese in pregnant women during first or second trimester and umbilical blood of fetal,and to investigate the relationship between prenatal arsenic and manganese exposure in different periods and sub-threshold autistic traits in toddlers at 18 month.MethodsThis study was based on Ma’anshan Birth Cohort（MABC）,a population-based prospective study.A total of 3 474 eligible pregnant women were recruited between May 2013 and September 2014.Pregnant women and their partner’s information,clinical assessment,anthropometry and biological samples were obtained at the first（≤14 gestation week）,second（24²8 gestation week）and third（34³8 gestation week）trimester,and neonatal outcome information were extracted form hospital delivery records.Serum arsenic and manganese concentrations in first and second trimester and umbilical blood were detected via inductively coupled plasma mass spectrometry（ICP-MS）,and assessed sub-threshold autistic traits of toddlers at 18 months using the Checklist for Autism in Toddlers-23（CHAT-23）.Excluded termination of pregnancy（n=162）,gemellary pregnancy（n=39）,and toddlers who did not complete sub-threshold autistic traits assessment（n=197）,3 076 maternal-toddler pairs were included in this study finally.Due to partial blood samples were not provided in the first,second trimester and umbilical blood,there are 2 794 cases in first trimester,2 934 cases in second trimester and 2 581 umbilical blood cases were included in the finally analysis.Logistic regression model and restricted cubic spine model were used to analyze the relationship between prenatal arsenic and manganese exposure and sub-threshold autistic traits in toddlers.Serum arsenic levels were divided into high exposure group(≥P₅₀)and low exposure group(<P₅₀),to further explore the effects of manganese on sub-threshold autistic traits at different arsenic levels.ResultsMedian and interquartile ranges[P₅₀(P₂₅^P₇₅)]of serum arsenic in first,second trimester and umbilical blood were 1.75（1.22².51）μg/L,1.77（1.28².54）μg/L and1.88（1.28².89）μg/L,respectively;and the concentrations of serum manganese were2.77（2.01⁴.10）μg/L,2.66（2.06³.64）μg/L and 5.44（4.49⁶.79）μg/L,respectively.There were no significant difference between serum arsenic levels in maternal during first and second trimester and umbilical blood of fetal.The association between serum manganese in first trimester and the risk of sub-threshold autistic traits followed a U-shape dose-response curve after adjustment for potential confounders,meanwhile,there existed a J-shape dose-response relationship between umbilical blood manganese levels and the risk of sub-threshold autistic traits,but no significant relationship were observed between serum manganese level in second trimester and the risk of sub-threshold autistic traits in toddlers.Logistic regression analysis indicated that high manganese exposure in umbilical blood had an increased risk of sub-threshold autistic traits（OR=1.45,95%CI:1.06¹.99）,the difference was statistically significant after adjusting for potential confounders.Stratified analysis showed that low manganese level in first trimester increased the risk of sub-threshold autistic traits（OR=1.62,P=0.037）,and the risk of high manganese exposure in umbilical blood became more significant（OR=1.97,95%CI:1.25³.11）when serum arsenic level were higher.After further gender stratification,the difference only appeared in boys rather than girls.In sensitivity analyses,we reran the model removing the outliers of serum manganese concentrations,and adjustment for serum lead（Ln-Pb）and mercury（Ln-Hg）levels in regression models,associations between prenatal manganese exposure levels and sub-threshold autistic traits remained similar.ConclusionOur findings suggest that prenatal manganese exposure have adverse and sex-specific effects on sub-threshold autistic traits in toddlers,and the associations were even stronger when arsenic levels were high,indicted that there may be a synergistic interaction between arsenic and manganese on the risk of sub-threshold autistic traits.Future studies should focus on the impact of metals co-exposure on neurodevelopment of children.