VITO Health, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium; Toxicological Centre, University of Antwerp, Universiteitsplein, 1, 2610 Wilrijk, Belgium.
VITO Health, Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium.
Sci Total Environ. 2024 Jun 15;929:172426. doi: 10.1016/j.scitotenv.2024.172426. Epub 2024 Apr 15.
Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated.
To investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies.
In 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed.
The LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): -2.8 (-4.2;-0.4); MEHP: -1.4 (-3.4,0.2)] and higher FSH [∑DINP: 11.8 (-0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [-4.28 (-8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: -12.22 (-21.09;-1.18); oxo-MEHP: -12.73 (-22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males.
We observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.
邻苯二甲酸酯/DINCH 代谢物的暴露会导致人类生殖毒性，但其内分泌干扰机制尚未完全阐明。
研究来自 HBM4EU 三个一致研究的欧洲青少年尿液中邻苯二甲酸酯/DINCH 代谢物浓度与血清 kisspeptin 和生殖激素之间的关系。
在 733 名比利时（FLEHS IV 研究）、斯洛伐克（PCB 队列随访）和西班牙（BEA 研究）青少年中，通过高效液相色谱-串联质谱法测定尿液中 10 种邻苯二甲酸酯和 2 种 DINCH 代谢物的浓度。采用免疫吸附法测定血清 kisspeptin（kiss54）蛋白、卵泡刺激素（FSH）、总睾酮（TT）、雌二醇（E2）和性激素结合球蛋白（SHBG）水平。通过计算游离雄激素指数（FAI）来估算游离睾酮。对个体研究进行了调整后的性别分层线性回归模型，对汇总研究进行了混合效应模型（LME），以考虑随机效应，并对邻苯二甲酸酯/DINCH 混合物进行了 g 计算和贝叶斯核机器回归（BKMR）模型分析。
LME 表明，ln 转化水平中几种邻苯二甲酸酯每增加一个 IQR，与女性 kisspeptin 水平降低相关[MnBP：%变化（95%CI）：-2.8（-4.2；-0.4）；MEHP：-1.4（-3.4，0.2）]和 FSH 水平升高相关[∑DINP：11.8（-0.6；25.1）]。g 计算表明，邻苯二甲酸酯/DINCH 混合物与女性 kisspeptin 水平降低相关[-4.28（-8.07；-0.34）]和 FSH 水平升高相关[22.13（0.5；48.4）]；BKMR 也显示出类似但不显著的模式。在男性中，较高的邻苯二甲酸酯代谢物[MEHP：-12.22（-21.09；-1.18）；oxo-MEHP：-12.73（-22.34；-1.93）]与 TT 和 FAI 降低有关，尽管较高的 DINCH [OH-MINCH：16.31（6.23；27.35），cx-MINCH：16.80（7.03；27.46），∑DINCH：17.37（7.26；29.74）]与 TT 水平升高有关。在男性中未发现混合物的相关性。
我们观察到尿液中邻苯二甲酸酯/DINCH 代谢物浓度与所选效应生物标志物（kisspeptin 和生殖激素）之间存在性别特异性关联。这表明，邻苯二甲酸酯的暴露可能与 kisspeptin 水平的变化有关，这将影响 HPG 轴，从而影响生殖健康。然而，还需要进一步的研究，特别是对于邻苯二甲酸酯替代品，如 DINCH。
