Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
Environ Res. 2022 Sep;212(Pt B):113342. doi: 10.1016/j.envres.2022.113342. Epub 2022 Apr 22.
Phthalate exposure has been associated with adverse reproductive outcomes and oxidative stress is a potential mechanism by which they act. However, few human studies have explored co-exposure confounding or joint effects. Furthermore, most studies examine associations between biomarkers of exposure and oxidative stress from the same urine sample. We investigated single-exposure, co-exposure-adjusted, and joint associations between phthalate metabolites and oxidative stress in the Environment and Reproductive Health (EARTH) study among couples undergoing fertility treatment. We examined cross-sectional associations in both women and men, and longitudinal associations in women. Urine was collected in the follicular phase (women only) and at the time of fertility procedure (women and men), and analyzed for 11 phthalate metabolites. Urine from the time of fertility procedure was analyzed for oxidative stress biomarkers, including free 8-iso-prostaglandin F (8-iso-PGF), its primary metabolite (2,3-dinor-5,6-dihydro-15-F-isoprostane [F-IsoP-M]), and prostaglandin F (PGF). Linear mixed effects models were used to estimate single-exposure associations. Bayesian Kernel Machine Regression (BKMR) was used to adjust for co-exposures and to estimate joint effects. Among women, we observed positive associations between all phthalate metabolites and oxidative stress biomarkers in single-exposure models, but there was clear co-exposure confounding. For instance, in a single-exposure model, we estimated a 63% (95% confidence interval: 51, 77) increase in the 8-iso-PGF metabolite per interquartile range (IQR) difference in mono-n-butyl phthalate (MBP) versus a 34% (95% credible interval: 12, 60) increase in co-adjusted models. However, several phthalate metabolites remained associated with oxidative stress in co-exposure models, and the joint effects of all exposures were high (e.g., an 114% increase in the 8-iso-PGF metabolite per IQR difference in all exposures). Longitudinal results were also attenuated compared to cross-sectional results in women; however, the joint effect of all exposures and the 8-iso-PGF metabolite remained positive and statistically significant (11% increase per IQR difference in all exposures, 95% credible interval: 0.2, 23). In men, associations were generally less pronounced, although the joint effect of the mixture on 8-iso-PGF was above the null. Because oxidative stress is related to reproductive success among couples seeking fertility treatment, mitigating phthalate exposure should be considered as a potentially beneficial measure.
邻苯二甲酸酯暴露与不良生殖结局有关，氧化应激是其作用的潜在机制。然而，很少有人类研究探讨共同暴露的混杂或联合效应。此外，大多数研究都从同一尿液样本中检查暴露生物标志物与氧化应激之间的关联。我们在环境与生殖健康（EARTH）研究中调查了在接受生育治疗的夫妇中，邻苯二甲酸酯代谢物与氧化应激之间的单一暴露、共同暴露调整和联合关联。我们在女性和男性中都检查了横断面关联，并在女性中检查了纵向关联。在卵泡期（仅限女性）和生育过程中（女性和男性）采集尿液，并对 11 种邻苯二甲酸酯代谢物进行分析。在生育过程中采集的尿液用于分析氧化应激生物标志物，包括游离 8-异前列腺素 F（8-iso-PGF）、其主要代谢物（2,3-二去-5,6-二氢-15-F-前列腺素 [F-IsoP-M]）和前列腺素 F（PGF）。线性混合效应模型用于估计单一暴露关联。贝叶斯核机器回归（BKMR）用于调整共同暴露并估计联合效应。在女性中，我们在单一暴露模型中观察到所有邻苯二甲酸酯代谢物与氧化应激生物标志物之间存在正相关，但存在明显的共同暴露混杂。例如，在单一暴露模型中，我们估计与单丁基邻苯二甲酸酯（MBP）每四分位距（IQR）差异相比，8-iso-PGF 代谢物增加 63%（95%置信区间：51,77），而在共同调整模型中，8-iso-PGF 代谢物增加 34%（95%可信区间：12,60）。然而，在共同暴露模型中，一些邻苯二甲酸酯代谢物仍与氧化应激相关，并且所有暴露的联合效应很高（例如，所有暴露的 IQR 差异增加 114%，8-iso-PGF 代谢物增加 114%）。与女性的横断面结果相比，纵向结果也减弱了；然而，所有暴露和 8-iso-PGF 代谢物的联合效应仍然为正且具有统计学意义（所有暴露的 IQR 差异增加 11%，95%可信区间：0.2,23）。在男性中，关联通常不太明显，尽管混合物对 8-iso-PGF 的联合效应高于零。由于氧化应激与寻求生育治疗的夫妇的生殖成功有关，因此应考虑减轻邻苯二甲酸酯暴露，作为一种潜在有益的措施。
