Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF
Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF
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DOI：
10.1093/humrep/des328
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发表时间：
2012-12-01
影响因子：
6.1
通讯作者：
Hauser, Russ
中科院分区：
文献类型：
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作者：
Ehrlich, Shelley;Williams, Paige L.;Hauser, Russ
在接受IVF的女性中，尿双酚A（BPA）浓度与卵巢反应和早期生殖结果（包括卵母细胞成熟和受精、第3天胚胎质量和囊胚形成）相关吗？较高的尿BPA浓度与卵巢反应性降低、受精卵数量减少和胚泡形成减少有关。实验动物和体外研究报告了BPA暴露与不良生殖结果之间的关系。我们以前曾报道过接受IVF的女性中尿BPA与卵巢反应降低[血清雌二醇（E-2）峰值和取卵时的卵母细胞计数]之间存在相关性;然而，关于生殖健康结局（如受精和胚胎发育）的人类数据有限。2004年11月至2010年8月期间，在美国马萨诸塞州波士顿的马萨诸塞州综合医院生育中心招募了174名年龄为18 - 45岁并接受237个IVF周期的女性。这些妇女被跟踪，直到他们有一个活产或停止治疗。分析中不包括冷冻和捐赠卵子周期。尿液BPA浓度采用在线固相萃取-高效液相色谱-同位素稀释-串联质谱法测量。在适当的情况下，使用混合效应模型、泊松回归和多变量逻辑回归模型来评估周期特异性尿BPA浓度与卵巢反应、卵母细胞成熟（中期II）、受精、胚胎质量和卵裂率指标之间的相关性。我们使用广义估计方程解释了同一女性多个IVF周期之间的相关性。尿BPA浓度的几何平均值（SD）为1.50（2.22）g/l。校正年龄和其他潜在混杂因素后（第3天血清FSH，吸烟，BMI），尿BPA浓度增加与卵母细胞数量减少之间存在显著的线性剂量反应关系（总体和成熟），正常受精的卵母细胞数量减少，E-2水平降低（与最低四分位数相比，尿BPA四分位数2、3和4分别平均降低40、253和471 pg/ml;趋势P值0.001）。对于尿BPA的最高四分位数与最低四分位数，卵母细胞和正常受精卵母细胞的平均数量分别减少24和27（趋势检验P分别为0.001和0.002）。尿BPA高于最低四分位数的妇女囊胚形成减少（趋势检验P值0.08）。潜在的局限性包括由于BPA的半衰期非常短及其随时间的高度可变性而导致的暴露错误分类;不确定性的普遍性的结果，以妇女的一般人口自然受孕和有限的样本。结果，从这个扩展的研究，使用IVF作为研究人类早期生殖健康结果的模型，表明尿BPA浓度与血清峰值E-2和卵母细胞产量之间存在负剂量反应关系，证实了我们先前的发现。此外，我们发现中期II卵母细胞计数和正常发育的卵母细胞数量显著减少，并提示BPA尿浓度与囊胚形成减少之间存在关联，因此表明BPA可能会改变接受IVF的易感妇女的生殖功能。这项工作得到了国家环境健康科学研究所的赠款ES 009718和ES 000002，OH 008578，来自国家职业安全和健康研究所。没有任何作者有实际或潜在的竞争性经济利益。免责声明：本报告中的发现和结论是作者的发现和结论，不一定代表疾病控制和预防中心的观点。
In women undergoing IVF, are urinary bisphenol A (BPA) concentrations associated with ovarian response and early reproductive outcomes, including oocyte maturation and fertilization, Day 3 embryo quality and blastocyst formation?Higher urinary BPA concentrations were found to be associated with decreased ovarian response, number of fertilized oocytes and decreased blastocyst formation.Experimental animal and in vitro studies have reported associations between BPA exposure and adverse reproductive outcomes. We previously reported an association between urinary BPA and decreased ovarian response [peak serum estradiol (E-2) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limited human data on reproductive health outcomes, such as fertilization and embryo development.Prospective preconception cohort study. One hundred and seventy-four women aged 1845 years and undergoing 237 IVF cycles were recruited at the Massachusetts General Hospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010. These women were followed until they either had a live birth or discontinued treatment. Cryothaw and donor egg cycles were not included in the analysis.Urinary BPA concentrations were measured by online solid-phase extraction-high-performance liquid chromatography-isotope dilution-tandem mass spectrometry. Mixed effect models, poisson regression and multivariate logistic regression models were used wherever appropriate to evaluate the association between cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation (metaphase II), fertilization, embryo quality and cleavage rate. We accounted for correlation among multiple IVF cycles in the same woman using generalized estimating equations.The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) g/l. After adjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was a significant linear doseresponse association between increased urinary BPA concentrations and decreased number of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreased E-2 levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, when compared with the lowest quartile, respectively; P-value for trend 0.001). The mean number of oocytes and normally fertilized oocytes decreased by 24 and 27, respectively, for the highest versus the lowest quartile of urinary BPA (trend test P 0.001 and 0.002, respectively). Women with urinary BPA above the lowest quartile had decreased blastocyst formation (trend test P-value 0.08).Potential limitations include exposure misclassification due to the very short half-life of BPA and its high variability over time; uncertainty about the generalizability of the results to the general population of women conceiving naturally and limited sample.The results from this extended study, using IVF as a model to study early reproductive health outcomes in humans, indicate a negative doseresponse association between urinary BPA concentrations and serum peak E-2 and oocyte yield, confirming our previous findings. In addition, we found significantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and a suggestive association between BPA urinary concentrations and decreased blastocyst formation, thus indicating that BPA may alter reproductive function in susceptible women undergoing IVF.This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and grant OH008578 from the National Institute for Occupational Safety and Health. None of the authors has actual or potential competing financial interests. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.