AHR gene-dioxin interactions and birthweight in the Seveso Second Generation Health Study
AHR gene-dioxin interactions and birthweight in the Seveso Second Generation Health Study
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DOI：
10.1093/ije/dyy165
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发表时间：
2018-12-01
影响因子：
7.7
通讯作者：
Eskenazi, Brenda
中科院分区：
文献类型：
--
作者：
Ames, Jennifer;Warner, Marcella;Eskenazi, Brenda
背景：2,3,7,8-四氯二苯并-对二恶英 (TCDD) 被认为通过改变芳烃受体（蛋白质：AHR；基因：AHR）途径的活性来干扰胎儿生长，该途径调节包括异生物质代谢在内的多种生物和发育过程。 AHR 的遗传变异是产前吸烟儿童易患低出生体重的一个重要驱动因素，但人们对这些与 AHR 最有效的异生配体 TCDD 的遗传相互作用知之甚少。 方法：塞维索妇女健康研究 (SWHS) 于 1996 年启动，研究了 981 名意大利妇女，她们在 1976 年 7 月的一次工业爆炸中暴露于 TCDD。我们测量了接近该时间收集的母体血清中 TCDD 的浓度。事故发生的原因。 2008 年和 2014 年，我们对 SWHS 队列进行了随访，并收集了 SWHS 意外怀孕妇女的出生结果数据。我们对 574 名 SWHS 母亲的 AHR 中的 19 个单核苷酸多态性 (SNP) 进行了基因分型。结果：在 901 名单胎新生儿中，单独的 SNP 和 TCDD 暴露均与出生体重显着相关。然而，我们在 AHR 中发现了 6 个单独的 SNP，它们对母亲 TCDD 和出生体重之间的关联产生了不利影响，暗示了基因与环境的相互作用。当我们检查这些 SNP 在风险等位基因评分中的共同贡献时，我们发现由于相互作用，对 TCDD 的敏感性更强。这些 SNP 均位于 AHR 的非编码区，特别是靠近启动子的区域。 结论：这是第一项证明母体 AHR 基因的遗传变异可能影响胎儿对 TCDD 暴露的敏感性的研究。
Background: 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is proposed to interfere with fetal growth via altered activity of the aryl hydrocarbon receptor (protein: AHR; gene: AHR) pathway which regulates diverse biological and developmental processes including xenobiotic metabolism. Genetic variation in AHR is an important driver of susceptibility to low birthweight in children exposed to prenatal smoking, but less is known about these genetic interactions with TCDD, AHR's most potent xenobiotic ligand.Methods: The Seveso Women's Health Study (SWHS), initiated in 1996, is a cohort of 981 Italian women exposed to TCDD from an industrial explosion in July 1976. We measured TCDD concentrations in maternal serum collected close to the time of the accident. In 2008 and 2014, we followed up the SWHS cohort and collected data on birth outcomes of SWHS women with post-accident pregnancies. We genotyped 19 single nucleotide polynnorphisms (SNPs) in AHR among the 574 SWHS mothers.Results: Among 901 singleton births, neither SNPs nor TCDD exposure alone were significantly associated with birthweight. However, we found six individual SNPs in AHR which adversely modified the association between maternal TCDD and birthweight, implicating gene-environment interaction. We saw an even stronger susceptibility to TCDD due to interaction when we examined the joint contribution of these SNPs in a risk allele score. These SNPs were all located in noncoding regions of AHR, particularly in proximity to the promoter.Conclusions: This is the first study to demonstrate that genetic variation across the maternal AHR gene may shape fetal susceptibilities to TCDD exposure.