Jensen Morten Søndergaard, Anand-Ivell Ravinder, Nørgaard-Pedersen Bent, Jönsson Bo A G, Bonde Jens Peter, Hougaard David M, Cohen Arieh, Lindh Christian H, Ivell Richard, Toft Gunnar
From the aDepartment of Pediatrics, Regional Hospital of Randers; bPerinatal Epidemiology Research Unit, Department of Pediatrics, Aarhus University Hospital, Skejby, Denmark; cSchool of Bioscience, University of Nottingham, United Kingdom; dDanish Center for Neonatal Screening, Department of Clinical Biochemistry and Immunology, Statens Serum Institute, Copenhagen, Denmark; eDivision of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden; fDepartment of Occupational and Environmental Medicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; gReproductive Endocrinology, Leibniz Institute for Farm Animal Biology, Dummerstorf, Germany; and hDanish Ramazzini Center, Department of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark.
Epidemiology. 2015 Jan;26(1):91-9. doi: 10.1097/EDE.0000000000000198.
Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to study prenatal di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) exposure in relation to cryptorchidism, hypospadias, and human fetal Leydig cell function.
We studied 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls. Second-trimester amniotic fluid samples were available from a Danish pregnancy-screening biobank (n = 25,105) covering 1980-1996. We assayed metabolites of DEHP and DiNP (n = 645) and steroid hormones (n = 545) by mass spectrometry. We assayed insulin-like factor 3 by immunoassay (n = 475) and analyzed data using linear or logistic regression.
Mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP, DEHP metabolite) was not consistently associated with cryptorchidism or hypospadias. However, we observed an 18% higher (95% confidence interval [CI] = 5%-33%) testosterone level, and a 41% lower (-56% to -21%) insulin-like factor 3 level in the highest 5cx-MEPP tertile compared with the lowest. Mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP, DiNP metabolite) showed elevated odds ratio point estimates for having cryptorchidism (odds ratio = 1.28 [95% CI = 0.80 to 2.01]) and hypospadias (1.69 [0.78 to 3.67]), but was not consistently associated with the steroid hormones or insulin-like factor 3.
Data on the DEHP metabolite indicate possible interference with human male fetal gonadal function. Considering the DiNP metabolite, we cannot exclude (nor statistically confirm) an association with hypospadias and, less strongly, with cryptorchidism.
孕期接触邻苯二甲酸盐可能对人类男性生殖构成威胁。然而，仍需要更多关于其对人体体内影响的知识，并且已报道的与生殖器异常的关联尚无定论。我们旨在研究孕期邻苯二甲酸二（2-乙基己基）酯（DEHP）和邻苯二甲酸二异壬酯（DiNP）暴露与隐睾症、尿道下裂以及人类胎儿睾丸间质细胞功能之间的关系。
我们研究了270例隐睾症病例、75例尿道下裂病例和300例对照。从丹麦一个涵盖1980 - 1996年的妊娠筛查生物样本库中获取了孕中期羊水样本（n = 25,105）。我们通过质谱法检测了DEHP和DiNP的代谢物（n = 645）以及类固醇激素（n = 545）。我们通过免疫分析法检测了胰岛素样因子3（n = 475），并使用线性或逻辑回归分析数据。
邻苯二甲酸单（2-乙基-5-羧基戊基）酯（5cx-MEPP，DEHP代谢物）与隐睾症或尿道下裂之间没有始终一致的关联。然而，我们观察到，与最低三分位数相比，最高三分位数的5cx-MEPP组中睾酮水平高18%（95%置信区间[CI] = 5% - 33%），胰岛素样因子3水平低41%（-56%至-21%）。邻苯二甲酸单（4-甲基-7-羧基庚基）酯（7cx-MMeHP，DiNP代谢物）显示隐睾症（优势比 = 1.28 [95% CI = 0.80至2.01]）和尿道下裂（1.69 [0.78至3.67]）的优势比点估计值升高，但与类固醇激素或胰岛素样因子3没有始终一致的关联。
关于DEHP代谢物的数据表明可能会干扰人类男性胎儿的性腺功能。考虑到DiNP代谢物，我们不能排除（也不能从统计学上证实）其与尿道下裂的关联，与隐睾症的关联则较弱。
