目的:妊娠期间母体尿异黄酮(ISO)浓度是否与出生时婴儿的肛门生殖器距离(AGD)有关,
结论:怀孕期间较高的孕妇尿ISO浓度与男女婴儿的AGD延长有关,雌马酚(EQU)和大豆苷元(DAD)被确定为观察到的关联中的重要ISO混合物成分。
背景:产前暴露于ISO与后代AGD相关的证据主要来自动物研究,使用不同的研究设计,结果不一致。据报道,只有一项人体研究发现,孕妇在怀孕期间的ISO暴露与出生时男孩的AGD之间没有关联。具有小样本量和宽范围的曝光窗口。没有发现对女孩的人类研究。
方法:前瞻性队列研究(上海-闵行出生队列研究),上海孕妇在妊娠12-16周招募,2012年4月至12月的中国。分娩时,队列中还剩下一千二百二十五个活的单身婴儿,其中480对母婴对具有有关母体尿ISO浓度和至少一次AGD测量的数据,并包括在本研究中。在出生时以及6个月和12个月大时,测量了男孩的阳极距离(AGDAP)和阳极距离(AGDAS)以及女孩的阳极距离(AGDAC)和阳极距离(AGDAF)。
方法:使用多元线性回归模型来检查母体ISO浓度与AGD之间的关联。实施贝叶斯核机回归(BKMR)以检查ISO混合物的整体效果和每个ISO的单个效果,并确定ISO混合物的重要成分。
结果:在男女婴儿中观察到较高浓度的母体ISO与较长的AGD有关。当母亲教育,奇偶校验,怀孕前的BMI(BMI,分类变量),怀孕早期被动吸烟,分娩年龄,调整孕周和婴儿体型.在男孩中,EQU与出生时以及6个月和12个月时的AGDAS增加有关,DAD与出生时AGDAP增加有关。在女孩中,研究发现EQU和DAD与出生时AGDAC和AGDAF增加相关.当前6个月婴儿的妊娠期体重增加和喂养方式进行额外调整时,母体BMI被调整为连续变量,观察到更明显的关联,特别是对于金雀异黄素(GEN)的协会,男孩在6个月时DAD和糖素(GLY)增加AGDAP和AGDAS。然而,这些关联并不总是在最高三元组中观察到,并且没有发现一致的剂量-反应关系。在BKMR模型中观察到类似的结果,在6个月和12个月的男孩中,ISO混合物的浓度与AGDAS的增加呈正相关,女孩出生时增加了AGDAC和AGDAF。在6个月时,男孩的AGDAS和女孩的AGDAC在6个月时具有统计学意义的增量为4.96mm(95%可信间隔(CrI):1.40,8.52)和1.07mm(95%CrI:0.02,2.13),分别,在ISO混合物的第75百分位数观察到,与第25百分位数相比。EQU和DAD被确定为ISO-AGD关联中的重要组成部分。
结论:首先,由于ISO的半衰期短,反映怀孕期间ISO暴露的单个点尿液样本的准确性可能有限,因此可能导致无差异错误分类。第二,尽管在研究中对几个重要的协变量进行了调整,不可测量的和残余的混杂因素可能仍然是一个问题。第三,由于多次测试导致的错误发现可能仍然存在。最后,减少的样本量归因于随访的丢失和混杂的数据缺失可能会限制我们检测关联的能力,如果有的话。
结论:产前ISO暴露可能影响子代的生殖发育。由于ISO可以在孕妇中广泛检测到,尤其是在东方国家,有必要进行更多研究,以提供产前ISO暴露对长期生殖结局影响的证据.
背景:这项工作得到了国家重点研究发展计划(2021YFC2701003)的资助,国家自然科学基金(22076123),上海市科学技术委员会(21ZR1454700和20ZR1448000),上海市卫生健康委员会(20194Y0160)和NHC生殖调节重点实验室(CX2022-04)的创新科技资助。作者没有利益冲突要声明。
背景:不适用。
Are maternal urinary
isoflavone (ISO) concentrations during pregnancy associated with anogenital distance (AGD) in infants at birth, and at 6 and 12 months of age?
Higher maternal urinary ISO concentrations during pregnancy were associated with longer AGD in infants of both sexes, and equol (EQU) and daidzein (DAD) were identified as the important ISO mixture components in the observed associations.
Evidence of the association of prenatal exposure to ISO with offspring\'s AGD is mainly derived from animal studies, which used different study designs and had inconsistent results. Only one human
study has been reported and it found null associations between maternal ISO exposure during pregnancy and AGD among boys at birth, with a small sample size and a wide range of exposure windows. No human
study on girls was found.
Prospective cohort
study (Shanghai-Minhang Birth Cohort
Study), with pregnant women recruited at 12-16 weeks of gestation in Shanghai, China between April and December 2012. One thousand two hundred and twenty-five live singletons were left in the cohort at delivery of which 480 mother-infant pairs had data on both maternal urinary ISO concentrations and at least one AGD measurement and were included in the present study. Anopenile distance (AGDAP) and anoscrotal distance (AGDAS) of boys and anoclitoral distance (AGDAC) and anofourchette distance (AGDAF) of girls were measured at birth and at 6 and 12 months of age.
Multiple linear regression models were used to examine the associations between maternal ISO concentrations and AGD. Bayesian kernel machine regression (BKMR) was implemented to examine both the overall effects of ISO mixture and the single effect of each ISO and identify important components of ISO mixture.
A general profile of higher concentrations of maternal ISO associated with longer AGD in infants of both sexes was observed, when maternal education, parity, BMI before pregnancy (BMI, categorical variable), passive smoking during early pregnancy, age at delivery, gestational weeks and infant body size were adjusted for. Among boys, EQU was associated with increased AGDAS at birth and at 6 and 12 months, and DAD was associated with increased AGDAP at birth. Among girls, the associations of EQU and DAD with increased AGDAC and AGDAF at birth were found. When gestational weight gain and feeding patterns of infants in the first 6 months were additionally adjusted for, and maternal BMI was adjusted for as a continuous variable, more pronounced associations were observed, especially for associations of genistein (GEN), DAD and glycitein (GLY) with increased AGDAP and AGDAS at 6 months in boys. However, these associations were not always observed in the highest tertile group, and no consistent dose-response relationships were found. Similar results were observed in BKMR models, showing positive correlations of concentration of ISO mixture with increased AGDAS at both 6 and 12 months among boys, and increased AGDAC and AGDAF at birth among girls. Statistically significant increments of 4.96 mm (95% credible interval (CrI): 1.40, 8.52) and 1.07 mm (95% CrI: 0.02, 2.13) in AGDAS at 6 months among boys and AGDAC at birth among girls, respectively, were observed at the 75th percentile of ISO mixture, compared with 25th percentile. EQU and DAD were identified as the important components among ISO-AGD associations.
First, due to the short half-lives of ISO, the accuracy of a single spot urine sample reflecting ISO exposure during pregnancy may be limited, and thus may cause non-differential misclassification. Second, despite the adjustments for several important covariates in the
study, unmeasured and residual confounding factors may remain a concern. Third, false discovery due to multiple testing may remain. Finally, the reduced sample sizes attributed to the loss of follow-up and missing data of confounders may limit our ability to detect an association, if any existed.
Prenatal ISO exposure may affect the reproductive development of offspring. As ISO can be widely detected in pregnant women, especially in Eastern countries, more studies are warranted to provide evidence of the effects of prenatal ISO exposure on long-term reproductive outcomes.
This work was supported by grants from the National Key Research and Development Program of China (2021YFC2701003), the National Natural Science Foundation of China (22076123), the Science and Technology Commission of Shanghai Municipality (21ZR1454700 and 20ZR1448000), the Shanghai Municipal Health Commission (20194Y0160) and Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2022-04). The authors have no conflicts of interest to declare.
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