不明原因复发性流产患者尿中双酚A和邻苯二甲酸酯代谢物与氧化应激生物标志物的关联研究

Association of urinary bisphenol A and phthalate metabolites with markers of oxidative stress in patients with unexplained recurrent spontaneous abortion

目的探讨不明原因复发性流产(unexplained recurrent spontaneous abortion,URSA)患者尿中双酚A(BPA)和邻苯二甲酸酯代谢物(mPAEs)水平与氧化应激生物标志物水平的关联。方法采用横断面研究方法,招募2018年4月至10月在首都医科大学附属北京妇产医院就诊的URSA患者为调查对象。采用超高效液相色谱—三重四极杆质谱法测定调查对象尿液中BPA和mPAEs水平,采用酶联免疫吸附法测定尿8-羟基脱氧鸟苷(8-OHdG)和8-异前列腺素F2α(8-iso-PGF2α)水平。采用多元线性回归模型和限制性立方样条函数评估尿BPA和mPAEs水平与8-OHdG和8-iso-PGF2α水平的关联。结果共纳入94名调查对象,年龄为(32.38±3.89)岁。多元线性回归结果表明,调整混杂因素后,URSA患者尿BPA和mPAEs水平均与尿8-OHdG和8-iso-PGF2α水平呈显著正向关联(P<0.05)。限制性立方样条函数分析结果显示,URSA患者尿8-OHdG水平与BPA水平呈正向关联(P_(总关联)=0.002),与邻苯二甲酸单(2-乙基-5-羟基己基)酯(MEHHP)、邻苯二甲酸单(2-乙基-5-氧己基)酯(MEOHP)和邻苯二甲酸单(2-乙基己基)酯(MEHP)水平均呈正向非线性关系(P_(非线性关联)=0.046,P_(非线性关联)=0.046,P_(非线性关联)=0.007),与邻苯二甲酸单甲酯(MMP)水平的关系呈“U”型(P_(非线性关联)=0.005);尿8-iso-PGF2α水平与BPA、邻苯二甲酸单异丁酯(MiBP)、MEHHP、MEOHP和MEHP水平均呈正向关联(P_(总关联)<0.05),与MMP水平的关系呈“U”型(P_(非线性关联)=0.006)。结论URSA患者尿BPA和mPAE水平与氧化应激生物标志物水平存在正向关联,但不同代谢产物的关联曲线特征不同。

Objective To investigate the relationship of the levels of urinary bisphenol A(BPA)and phthalate metabolites(mPAEs)with the levels of oxidative stress markers in patients with unexplained recurrent spontaneous abortion(URSA).Methods Using the cross-sectional study method,patients with URSA were recruited from Beijing Obstetrics and Gynecology Hospital of Capital Medical University from April to October in 2018.The concentrations of BPA and mPAEs in urine were determined by UPLC-MS,and the concentrations of 8-hydroxy-2-deoxyguanosine(8-OHdG)and 8-iso-prostaglandin F2α(8-iso-PGF2α)in urine were determined by enzyme-linked immunosorbent assay.Multiple linear regression model and restricted cubic spline functions were used to evaluate the relationship of BPA and mPAEs levels with 8-OHdG and 8-iso-PGF2αconcentrations in urine.Results A total of 94 participants were included,aged 32.38±3.89 years old.The result of multiple linear regression showed that after adjusting for confounding factors,the concentrations of urinary BPA and mPAEs were significantly positively correlated with urinary 8-OHdG and 8-iso-PGF2αin patients with URSA(all P<0.05).The result of restricted cubic spline functions analysis showed that urinary 8-OHdG in patients with URSA was a positively linear correlated with BPA(P_(total correlation)=0.002),a positively nonlinear correlated with urinary mono(2-ethyl-5-hydroxyhexyl)phthalate(MEHHP),mono(2-ethyl-5-oxohexyl)phthalate(MEOHP)and mono(2-ethylhexyl)phthalate(MEHP)(P_(nonlinear correlation)=0.046,P_(nonlinear correlation)=0.046,P_(nonlinear correlation)=0.007),and had a“U”type relationship with urinary monomethyl phthalate(MMP)(P_(nonlinear correlation)=0.005).There was a positive linear correlation between Urinary 8-iso-PGF2αand BPA,monoisobutyl phthalate(MiBP),MEHHP,MEOHP and MEHP(P_(total correlation)<0.05),and a“U”type relationship with urinary MMP(P_(nonlinear correlation)=0.006).Conclusion Urinary BPA and mPAE levels were significantly associated with oxidative stress biomarkers in patients with URSA,but the correlation curves were different for different metabolites.