Effects Of Prenatal And Postnatal Exposure To Organophosphate Pesticides On Children's Neurobehavioral Development

Objective:Organophosphate pesticides?OPs?have been developed and used widely in China.Animal studies have reported that in utero or early postnatal OP exposure could adversely affect offspring's neurobehavioral development.However,few epidemiological researches have been available on the association between prenatal or early postnatal OP exposure and children's neurobehavioral development and the results are inconsistent,maybe due to the suscepitibility to OPs.Paraoxonase 1?PON1?,a detoxifying enzyme of OPs,is gaining more and more attention in the population's susceptibility to OPs.In the present study,we measured urinary levels of six dialkylphosphate?DAP?metabolites in pregnant women and children at 24months of age,and examined the association between biomarkers of OPs,PON1,and developmental quotients?DQs?in 24-month-old children.We explored the role of brain-derived neurotrophic factor?BDNF?in the association of OP exposure and neurobehavioral development.Methods:The investigation was a prospective birth cohort study in the southern coastal area of Laizhou Wan?Bay?of the Bohai Sea,Shandong province,China?Laizhou Wan Birth Cohort,LWBC?.From September 2010 to December 2013,773pregnant women were recruited when admitted in labor at the only hospital of the area.Random spot urine specimens were collected during hospital admission for delivery from the pregnant women?n=436?and from children at 24 months of age?n=427?during follow-up visits.We analyzed six DAP metabolites by using the method of gas chromatography-mass spectrometry?GC-MS?in maternal and child urine specimens,and examined their relationships with developmental quotients?DQs?in gross motor,fine motor,adaptive,language,and social domains based on the Gesell Developmental Schedules?Gesell?in 24-month-old children.Maternal blood samples were obtained during hospital admission for delivery and were analyzed for PON1_-108,PON1₁₉₂,and PON1₅₅5 genotypes as well as DNA methylation?n=244?.We determined whether PON1 modified the association of prenatatl OP exposoure and neurobehavioral development.We measured BDNF concentrations in umbilical cord serum?n=364?,and determined whether BDNF was related with OPs.We determined the mediator effect of umbilical cord serum BDNF concentrations in the association between OPs and neurobehavioral development in 24-month-old children.Results:?1?The creatinine-adjusted median levels of DAP metabolites in maternal urine samples were 21.42?g/g for dimethylphosphate?DMP?,2.24?g/g for dimethylthiophosphate?DMTP?,11.41?g/g for diethylphosphate?DEP?,and 1.93?g/g for diethylthiophosphate?DETP?.The levels of major DAP metabolites?DMP and DEP?in the present study were much higher than those reported in the developed countries.?2?Prenatal diethylphosphate metabolites?DEs??DEs=DEP+DETP?were significantly negatively associated with social domain DQ scores in children at24 months of age.A 10-fold increase in prenatal DEs was associated with a 2.59-point?95%CI:–4.71 to–0.46?decrease in social domain DQ scores.Prenatal total dialkylphosphate metabolites?DAPs??DAPs=DMP+DMTP+DEP+DETP?were significantly negatively associated with social domain DQ scores in children at 24months of age.A 10-fold increase in prenatal DAPs was associated with a 2.49-point?95%CI:–4.85 to–0.14?decrease in social domain DQ scores.Prenatal DAPs??=–0.05,95%CI,–0.11 to–0.00,p=0.037?and DEs??=–0.06,95%CI,–0.10 to–0.01,p=0.016?were significantly negatively associated with umbilical cord serum BDNF concentrations.However,we did not find the mediator effect of umbilical cord serum BDNF concentrations in the association between prenatal OP exposure and neurobehavioral development in 24-month-old children.?3?The creatinine-adjusted median levels of DAP metabolites in 24-month-old children's urine samples were32.55?g/g for DMP,3.74?g/g for DMTP,14.81?g/g for DEP,and 3.93?g/g for DETP.The levels of major DAP metabolites?DMP and DEP?in the present study were much higher than those reported in the developed countries.?4?Postnatal dimethylphosphate metabolites?DMs??DMs=DMP+DMTP?were significantly positively associated with adaptive domain DQ scores in children at 24 months of age??=2.05,95%CI,0.41 to 3.69,p=0.014?.?5?Among 24-month-old children of mothers who carried the PON1_-108CC genotype,PON1₁₉₂QQ genotype,and PON1₅₅LM genotype,prenatal OP expoure was negatively associated with DQ scores:prenatal DMs were significantly negatively associated with social domain DQ scores in 24-month-old children of mothers who carried the PON1_-108CC genotype??=–5.72,95%CI,–11.29 to–0.16,p=0.044?;in 24-month-old children of mothers who carried the PON1₁₉₂QQ genotype,prenatal DMs??=–7.68,95%CI,–13.91 to–1.46,p=0.019?and prenatal DAPs??=–7.67,95%CI,–15.06 to–0.27,p=0.043?were significantly negatively associated with gross motor domain DQ scores,prenatal DMs??=–7.52,95%CI,–15.01 to–0.02,p=0.050?and prenatal DEs??=–9.07,95%CI,–17.51 to–0.63,p=0.037?as well as prenatal DAPs??=–9.60,95%CI,–17.92 to–1.29,p=0.027?were significantly negatively associated with social domain DQ scores;prenatal DMs were significantly negatively associated with fine motor domain DQ scores in 24-month-old children of mothers who carried the PON1₅₅LM genotype??=–6.94,95%CI,–13.54 to–0.35,p=0.040?.However,we did not find any significant associations between prenatal OP exposure and DQ scores among24-month-old children of mothers who carried the PON1_-108TT/CT genotype,PON1₁₉₂RR/QR genotype,and PON1₅₅MM genotype.?6?PON1 DNA methylation was associated with the PON1 genotype.Mothers who carried the PON1_-108CC genotype,PON1₁₉₂QQ genotype,and PON1₅₅LM genotype have lowest levels of methylation,whereas mothers with the PON1_-108CT genotype and PON1₁₉₂QR genotype have intermediate levels of methylation and mothers with PON1_-108TT genotype,PON1₁₉₂RR genotype,and PON1₅₅MM genotype have the highest levels of methylation.?7?Whether increased methylation may increase the suscepitibility of OP exposure on neurobehavioral development effects in offspring is inconsistent.Conclusions:The pregnant women and children in our study had significant higher levels of DAP metabolites compared with those reported in developed countries.Prenatal OP exposure could adversely affect children's neurobehavioral development at 24 months of age.These associations appeared to be enhanced among children of mothers who carried the PON1_-108CC,PON1₁₉₂QQ,and PON1₅₅LM genotype,suggesting that susceptibility to population should be considered in the study of neurobehavioral development effects of OP exposure.Prenatal OP exposure was negatively associated with umbilical cord serum BDNF concentrations.We did not find the mediator effect of umbilical cord serum BDNF concentrations in the association between prenatal OP exposure and neurobehavioral development in24-month-old children.