Role Of PON1 Genotype And Oxidative Stress In Effects Of Prenatal Exposure To Organophosphate Pesticides On Infants' Birth Outcomes

Objective:Organophosphate pesticides?OPs?are one of the most widely used class of pesticides in China.Animal studies and epidemiological studies have indicated that OP exposure may have adverse impacts on fetal development,but the results are inconsistent and the mechanism is still not clear.Some studies suggested that individual susceptibility to OPs may contribute to the inconsistent results.Paraoxonase 1?PON1?works as a detoxifying enzyme of OPs,whose gene polymorphism may influence individual suscepitibility to OPs.In addition,oxidative stress is also considered to be a possible mechanism of the adverse birth outcomes induced by OP exposure.In this study,we measured the levels of dialkylphosphate?DAP?metabolites of OPs in urine of pregnant women,analyzed the impacts of prenatal OP exposure on infants'birth outcomes.We also determined PON1 gene polymorphism and oxidative stress marker levels in pregnant women,and further explored the role of PON1 gene polymorphism and oxidative stress in the impacts of prenatal OP exposure on fetal development.Methods:This investigation was based on Laizhou Wan birth cohort study conducted in the southern coastal area of Laizhou Wan?Bay?of the Bohai Sea,Shandong Province,which enrolled 773 pregnant women in the third trimester from September2010 to December 2013 at the only hospital with maternity wards in this area.They were interviewed face to face using questionnaire and blood samples and urine samples were collected.The birth outcomes?gestational age,birth weight,length,ponderal index,head circumference and chest circumference?of their infants were followed up.We analyzed levels of urinary DAP metabolites?including dimethylphosphate?DMP?,dimethylthiophosphate?DMTP?,dimethyldithiophosphate?DMDTP?,diethylphosphate?DEP?,diethylthiophosphate?DETP?,diethyldithiophosphate?DEDTP??by gas chromatography-mass spectrometry as well as genotypes of PON1_-108,PON1₁₉₂ and PON1₅₅5 by DNA sequencing in 244 women.In addition,we measured the serum levels of two oxidative stress markers,total free sulfhydryl?-SH?and malondialdehyde?MDA?in 204 of the 244 women.We explored the relationship between DAP metabolite levels and infant's birth outcomes in all women?n=244?or women within each PON1 genotype by using linear regression models.We also analyzed the role of oxidative stress in the association between OP exposure and infants'birth outcomes?n=204?.Results:?1?Maternal levels of dimethyl phosphates?DMs,DMs=DMP+DMTP?were negatively associated with the gestational age[??95%CI?:-0.34?-0.66,-0.02?]?n=244?.After stratifying the study population by maternal genotypes of PON1_-108,PON1₁₉₂ and PON1₅₅,we found that maternal levels of diethyl phosphates?DEs,DEs=DEP+DETP?were negatively associated with infants'birth length[??95%CI?:-1.76?-3.09,-0.44?]among women with PON1_-108CC genotype;however,this association wasn't found among women with PON1₁₉₂CT and PON1₁₉₂TT genotypes.Maternal levels of DEs were negatively associated with infants'head circumference[??95%CI?:-1.03?-2.06,-0.01?]among women with PON1₅₅LM genotype;however,this association wasn't found among women with PON1₅₅MM genotype.We didn't find the association between maternal DAP metabolite levels and any of the birth outcomes?gestational age,birth weight,length,ponderal index,head circumference and chest circumference?among women with any kind of PON1₁₉₂ genotypes.?2?We failed to find the association between maternal DAP metabolite levels and oxidative stress marker levels,and didn't observe the association between oxidative stress marker levels and infants'birth outcomes?n=204?.Conclusion:Prenatal OP exposure may have adverse impacts on infants'birth outcomes,and these impacts were more obvious among pregnant women with PON1_-108C allele and PON1₅₅L allele,indicating that studies on the developmental toxicity of OP exposure should considered individual suscepitibility.The role of oxidative stress in the impacts of prenatal OP exposure on birth outcomes still needs further identification.