芳基有机磷酸酯暴露对体外受精女性生殖健康影响

Effects of aryl organophosphate ester exposure on female reproductive health by 571 infertile women in vitro fertilization from January 2018 January 2021

目的分析芳基有机磷酸酯(aryl-OPEs)对女性生殖健康的影响。方法对2018年1月—2021年1月就诊北京大学人民医院生殖中心的571例因不孕症拟行体外授精胚胎移植治疗的女性尿液样品进行aryl-OPEs4种代谢产物[磷酸二苯酯(DPHP)、4-羟基苯基二苯基磷酸酯(4-OH-TPHP)、2-乙基-5-羟基已基二苯基磷酸酯(5-OH-EHDPP)、4-(羟甲基)苯基二对甲苯磷酸酯(4-OH-MDTP)]浓度检测,将连续型自变量数据进行等级变量转换,以25%、50%和75%分位数作为分割点划分为4个等级(Q1,Q2,Q3,Q4),对每个组的自变量进行重新赋值后以连续型变量的形式代入回归模型当中,进行趋势检验。应用多元线性混合模型,通过调整相关协变量(年龄、BMI、吸烟情况、教育程度、不孕原因和原发不孕诊断),评估aryl-OPEs代谢物的浓度与生殖激素[雌二醇(E2)、孕酮(P)、睾酮(T)、卵泡刺激素(FSH)、黄体生成素(LH)、泌乳素(PRL)]及不孕病因的相关性。结果Aryl-OPEs 4种代谢产物的检出率均>80%。多元线性回归模型结果显示,尿液中4-OH-MDTP和5-OH-EHDPP的浓度与E2水平的降低有关(P<0.05),4-OH-MDTP Q3组比Q1组E2水平显著降低20.59%,5-OH-EHDPP Q4组较Q1组下降34.52%。4-OH-TPHP和DPHP暴露浓度与孕酮水平呈显著正相关趋势(P<0.05),4-OH-TPHP Q3的孕酮水平较Q1组显著增加42.42%,DPHP Q4组相比Q1组的孕酮水平显著增加32.85%。在不孕症病因分析中,多囊卵巢综合征及子宫内膜异位症患者4-OH-TPHP和4-OH-MDTP的浓度明显高于因男方因素行体外授精的女性患者,且4-OH-TPHP和4-OH-MDTP Q2~Q4组浓度比Q1组浓度的多囊卵巢综合征与子宫内膜异位症的发病风险均有增加。结论Aryl-OPEs可干扰女性体内雌激素和孕酮水平,其本体和代谢物可能与多囊卵巢综合征、子宫内膜异位症的发生相关,可能是导致不孕症的原因之一。

Objective To analyze the effects of aryl organophosphate esters(aryl-OPEs)on female reproductive health.Methods Urine samples from 571 women with infertility who sought in vitro fertilization-embryo transfer treatment at the Reproductive Center of Peking University People's Hospital from January 2018 to January 2021 were tested for concentrations of four aryl-OPE metabolites:diphenyl phosphate(DPHP),4-hydroxyphenyl diphenyl phosphate(4-OHTPHP),2-ethyl-5-hydroxyhexyl diphenyl phosphate(5-OH-EHDPP),and 4-(hydroxymethyl)phenyl di-p-tolyl phosphate(4-OH-MDTP).Continuous independent variable data were converted into categorical variables,divided into four levels(Q1,Q2,Q3,Q4)using the 25th,50th,and 75th percentiles as cut-off points.After reassigning values to the independent variables in each group,they were incorporated into the regression model as continuous variables for trend testing.Using multivariable linear mixed models,the correlations between aryl-OPE metabolite concentrations and reproductive hormones[estradiol(E2),progesterone(P),testosterone(T),follicle-stimulating hormone(FSH),luteinizing hormone(LH),and prolactin(PRL)and infertility causes were assessed by adjusting for relevant covariates(age,BMI,smoking status,education level,infertility reason,and primary infertility diagnosis).Results The detection rates of the four aryl-OPE metabolites were all>80%.The results of the multivariable linear regression model showed that the concentrations of 4-OH-MDTP and 5-OH-EHDPP in urine were associated with decreased E2 levels(P<0.05).The E2 level in the 4-OH-MDTP Q3 group was significantly lower by 20.59%compared to the Q1 group,and in the 5-OH-EHDPP Q4 group,it decreased by 34.52%compared to the Q1 group.The exposure concentrations of 4-OH-TPHP and DPHP showed a significant positive correlation with progesterone levels(P<0.05).The progesterone level in the 4-OH-TPHP Q3 group was significantly increased by 42.42%compared to the Q1 group,and in the DPHP Q4 group,it was significantly increased by 32.85%compared to the Q1 group.In the analysis of infertility causes,the concentrations of 4-OH-TPHP and 4-OH-MDTP in patients with polycystic ovary syndrome(PCOS)and endometriosis were significantly higher than those in women undergoing in vitro fertilization due to male factors.Moreover,the risk of PCOS and endometriosis increased in the 4-OH-TPHP and 4-OH-MDTP Q2-Q4 groups compared to the Q1 group.Conclusion Aryl-OPEs can interfere with estrogen and progesterone levels in women.The parent compounds and metabolites may be associated with the occurrence of PCOS and endometriosis and could be one of the causes of infertility.