Ao Junjie, Qiu Wei, Huo Xiaona, Wang Yuqing, Wang Wenjuan, Zhang Qianlong, Liu Zhiwei, Zhang Jun
Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
School of Public Health, Shanghai Jiao Tong University, Shanghai, China.
Hum Reprod. 2023 Apr 3;38(4):726-738. doi: 10.1093/humrep/dead016.
Is pre-conception exposure to parabens associated with fecundity in couples of childbearing age?
Paraben exposure in female partners was associated with reduced couple fecundity and anti-Müllerian hormone (AMH) might be one of the possible mediators.
The reproductive toxicity of parabens, a class of widely used preservatives, has been suggested but evidence regarding their effects on couple fecundity is scarce.
STUDY DESIGN, SIZE, DURATION: In this couple-based prospective cohort study, a total of 884 pre-conception couples who participated in the Shanghai Birth Cohort between 2013 and 2015 were included.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Concentrations of six parabens were measured in urine samples collected from couples. Malondialdehyde, C-reactive protein, and AMH were assessed in female partners. The outcomes included couple fecundability (time-to-pregnancy, TTP) and infertility (TTP > 12 menstrual cycles). Partner-specific and couple-based models were applied to estimate the associations. The joint effect of paraben mixture on couple fecundity was estimated by quantile-based g-computation (q-gcomp). Mediation analysis was used to assess the mediating roles of oxidative stress, inflammation and ovarian reserve.
A total of 525 couples (59.4%) conceived spontaneously. In the partner-specific model, propyl paraben (PrP), butyl paraben (BuP), and heptyl paraben (HeP) in female partners were associated with reduced fecundability (fecundability odds ratio (95% CI): 0.96 (0.94-0.98) for PrP; 0.90 (0.87-0.94) for BuP; 0.42 (0.28-0.65) for HeP) and increased risk of infertility (rate ratio (95% CI): 1.06 (1.03-1.10) for PrP; 1.14 (1.08-1.21) for BuP; 1.89 (1.26-2.83) for HeP). Similar associations were observed in the couple-based model. AMH played a significant mediation role in the association (average causal mediation effect (95% CI): 0.001 (0.0001-0.003)). Paraben exposure in male partners was not associated with couple fecundity. The joint effect of paraben mixture on couple fecundity was non-significant.
LIMITATIONS, REASONS FOR CAUTION: Self-reported pregnancy and single urine sample may lead to misclassification. The mediation analysis is limited in that levels of sex hormones were not measured. The inclusion of women with irregular menstrual cycles might affect the results. It is possible that the observed association was due to reverse causation.
This is the first study to assess the effects of paraben exposure on couple fecundity in Asians. Given the widespread exposure to parabens in couples of childbearing age, the present findings may have important public health implications.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by the National Natural Science Foundation of China (41991314), the Shanghai Science and Technology Development Foundation (22YF1426700), the Science and Technology Commission of Shanghai Municipality (21410713500), and the Shanghai Municipal Health Commission (2020CXJQ01). All authors declare no conflict of interest.
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育龄夫妇受孕前接触对羟基苯甲酸酯是否与生育力有关？
女性伴侣接触对羟基苯甲酸酯与夫妇生育力降低有关，抗苗勒管激素（AMH）可能是其中一个潜在中介因素。
对羟基苯甲酸酯是一类广泛使用的防腐剂，其生殖毒性已受到关注，但关于其对夫妇生育力影响的证据尚少。
研究设计、规模、持续时间：在这项基于夫妇的前瞻性队列研究中，纳入了2013年至2015年间参与上海出生队列的884对受孕前夫妇。
研究对象/材料、地点、方法：检测夫妇尿液样本中六种对羟基苯甲酸酯的浓度。对女性伴侣评估丙二醛、C反应蛋白和AMH。结局指标包括夫妇受孕能力（受孕时间，TTP）和不孕（TTP＞12个月经周期）。采用伴侣特异性模型和基于夫妇的模型来估计相关性。通过基于分位数的g计算（q-gcomp）估计对羟基苯甲酸酯混合物对夫妇生育力的联合效应。采用中介分析评估氧化应激、炎症和卵巢储备的中介作用。
共有525对夫妇（59.4%）自然受孕。在伴侣特异性模型中，女性伴侣中的对羟基苯甲酸丙酯（PrP）、对羟基苯甲酸丁酯（BuP）和对羟基苯甲酸庚酯（HeP）与受孕能力降低相关（受孕能力优势比（95%CI）：PrP为0.96（0.94 - 0.98）；BuP为0.90（0.87 - 0.94）；HeP为0.42（0.28 - 0.65）），且不孕风险增加（率比（95%CI）：PrP为1.06（1.03 - 1.10）；BuP为1.14（1.08 - 1.21）；HeP为1.89（1.26 - 2.83））。在基于夫妇的模型中观察到类似关联。AMH在该关联中起显著中介作用（平均因果中介效应（95%CI）：0.001（0.0001 - 0.003））。男性伴侣接触对羟基苯甲酸酯与夫妇生育力无关。对羟基苯甲酸酯混合物对夫妇生育力的联合效应不显著。
局限性、注意事项：自我报告的妊娠情况和单次尿液样本可能导致分类错误。中介分析存在局限性，因为未测量性激素水平。纳入月经周期不规律的女性可能影响结果。观察到的关联可能是由于反向因果关系。
这是第一项评估对羟基苯甲酸酯暴露对亚洲夫妇生育力影响的研究。鉴于育龄夫妇普遍接触对羟基苯甲酸酯，本研究结果可能具有重要的公共卫生意义。
研究资金/利益冲突：本研究部分得到中国国家自然科学基金（41991314）、上海科技发展基金会（22YF1426700）、上海市科学技术委员会（21410713500）和上海市卫生健康委员会（2020CXJQ01）的支持。所有作者均声明无利益冲突。
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