STUDY QUESTION:Is there an association between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and fecundability and infertility among Seveso women and their daughters?

SUMMARY ANSWER:TCDD exposure is associated with a decrease in fecundability and increased risk of infertility in women, as well as their daughters.

WHAT IS KNOWN ALREADY:In animal studies, maternal exposure to TCDD is associated with decreased fertility in offspring. Effects of TCDD are mediated by activation of the aryl hydrocarbon receptor (AHR) pathway.

STUDY DESIGN, SIZE, DURATION:The Seveso Women's Health Study (SWHS) has followed 981 women exposed to TCDD in a 1976 accident since 1996. In 2014, we initiated the Seveso Second Generation Study to follow-up their children.

PARTICIPANTS/MATERIALS, SETTING, METHODS:We obtained information on pregnancy history including time of trying to conceive from SWHS women and their daughters who were 18 years or older. We considered TCDD exposure as initial 1976 serum TCDD concentration and estimated TCDD at pregnancy. We examined relationships of TCDD exposure with time to pregnancy (TTP, the monthly probability of conception within the first 12 months of trying) and infertility (≥12 months of trying to conceive). We also assessed contributions of polymorphisms in the AHR pathway via genetic risk score.

MAIN RESULTS AND THE ROLE OF CHANCE:Among SWHS women (n = 446), median TTP was 3 months and 18% reported taking ≥12 months to conceive. Initial 1976 TCDD (log10) was associated with longer TTP (adjusted fecundability odds ratio = 0.82; 95% CI 0.68-0.98) and increased risk of infertility (adjusted relative risk = 1.35; 95% CI 1.01-1.79). TCDD at pregnancy yielded similar associations. Among SWHS daughters (n = 66), median TTP was 2 months and 11% reported taking ≥12 months to conceive. Daughters showed similar, but non-significant, associations with maternal TCDD exposure.

LIMITATIONS, REASONS FOR CAUTION:A limitation of this study is time to pregnancy was reported retrospectively, although previous studies have found women are able to recall time to conception with a high degree of accuracy many years after the fact. The number of SWHS daughters who had a live birth was small and we were unable to examine fecundability of SWHS sons.

WIDER IMPLICATIONS OF THE FINDINGS:Consistent with previous findings in animal studies, our study found that TCDD exposure may be associated with decreased fertility in Seveso mothers and potentially in their daughters exposed in utero. There may be susceptible genetic subgroups. The literature has largely considered the genetics of the AHR pathway in the context of male fertility but not female fertility, despite strong biological plausibility. These findings should be replicated in larger populations and of different ancestry. Future studies in Seveso should examine the sons and the grandchildren of exposed mothers given the animal literature suggesting potential heritable epigenetic effects.

STUDY FUNDING/COMPETING INTEREST(S):This study was supported by grant numbers F06 TW02075-01 from the National Institutes of Health, R01 ES07171 and 2P30-ESO01896-17 from the National Institute of Environmental Health Sciences, R82471 from the U.S. Environmental Protection Agency and #2896 from Regione Lombardia and Fondazione Lombardia Ambiente, Milan, Italy. J.A. was supported by F31ES026488 from the National Institutes of Health. The authors declare they have no actual or potential competing financial interests.

TRIAL REGISTRATION NUMBER:N/A.

译文

研究问题:Seveso妇女及其女儿的2,3,7,8-四氯二苯并-对-二恶英(TCDD)暴露与生育能力和不育之间是否存在关联?

< strong>摘要答案:TCDD暴露与女性及其女儿的生育能力下降和不孕风险增加有关。

已经知道的信息:在动物研究中,母体接触TCDD与后代生育力下降有关。 TCDD的作用是由芳烃受体(AHR)途径的激活介导的。

研究设计,大小,持续时间:Seveso妇女健康研究(SWHS)跟踪了981名妇女暴露自1996年以来,在1976年的一次事故中导致TCDD死亡。2014年,我们发起了Seveso第二代研究,以随访他们的孩子。

参与者/材料,设置,方法:我们获得了信息怀孕史,包括尝试从SWHS怀孕的妇女及其18岁或18岁以上女儿的时间。我们将TCDD暴露作为1976年初始血清TCDD浓度,并在怀孕时估计TCDD。我们研究了TCDD暴露与怀孕时间(TTP,尝试的前12个月内每月受孕的概率)和不孕症(≥12个月的受孕)之间的关系。我们还通过遗传风险评分评估了AHR途径中多态性的贡献。

主要结果和机会的作用:在SWHS女性(n = 446)中,TTP中位数为3个月。 18%的人报告怀孕时间≥12个月。 1976年最初的TCDD(log10)与更长的TTP(调整的受孕几率= 0.82; 95%CI 0.68-0.98)和不孕风险增加(调整的相对风险= 1.35; 95%CI 1.01-1.79)相关。怀孕时的TCDD产生了相似的关联。在SWHS女儿中(n = 66),中位TTP为2个月,而11%的人报告怀孕时间≥12个月。女儿表现出与孕妇TCDD暴露相似但不显着的关联。

局限性,谨慎的原因:尽管先前的研究回顾性地报道了这项研究的局限性,但该研究是怀孕时间。事实证明,事实已经很多年了,女性能够以很高的精确度回想起受孕的时间。有活产的SWHS女儿数量很少,我们无法检查SWHS儿子的生育能力。

发现的广泛意义:与先前在动物研究中的发现一致,我们的研究发现,在塞维索(Seveso)母亲中以及在子宫内暴露的女儿中,TCDD暴露可能与生育能力下降有关。可能存在易感的遗传亚群。尽管生物学上的可信度很高,但文献在很大程度上考虑了男性生殖力而非女性生殖力的AHR途径的遗传学。这些发现应在更大的人群和不同的血统中重复使用。鉴于动物文献表明潜在的遗传后生效应,Seveso的未来研究应检查裸露母亲的儿子和孙子。

研究资金/竞争兴趣:该研究得到了支持由美国国立卫生研究院(National Institutes of Institute)授予的F06 TW02075-01,美国国家环境卫生科学研究所(NIH)的R01 ES07171和2P30-ESO01896-17,美国环境保护局的R82471和来自米兰的Regione Lombardia和Fondazione Lombardia Ambiente的#2896 , 意大利。 J.A.由美国国立卫生研究院的F31ES026488支持。作者声明他们没有实际或潜在的竞争性财务利益。

试验注册号:不适用。

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