School of Public Health, Division of Epidemiology and Biostatistics, San Diego State University, San Diego, California, USA.
UC San Diego Moores Cancer Center, La Jolla, California, USA.
Mol Carcinog. 2022 Nov;61(11):1002-1015. doi: 10.1002/mc.23456. Epub 2022 Aug 17.
Parabens are a group of alkyl esters of p-hydroxybenzoic acid added to consumer products to prevent the growth of harmful bacteria and molds. Parabens are hypothesized to increase the risk of breast cancer (BC); however, no study has examined the interactions between parabens, global DNA methylation (DNAm), and BC risk. We examined the modifying effects of DNAm on the associations between parabens and BC, and whether parabens were associated with BC defined by tumor promoter methylation status. Participants included 708 cases and 598 controls from the Long Island Breast Cancer Study Project. Methylparaben (MPB), propylparaben, and butylparaben levels were measured in spot urine samples. Global DNAm was measured by analysis of long interspersed elementes-1 (LINE-1) and the luminometric methylation assay (LUMA). The promoter methylation status of 13 genes was measured in tumor samples from 509 cases. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between parabens and BC stratified by LINE-1/LUMA, and between parabens and gene-specific promoter methylation-defined BC. Outcome heterogeneity was evaluated using ratios of ORs (RORs). We assessed the joint effects of the multiple parabens using quantile g-computation. The highest versus lowest tertile of MPB and a one-quantile increase in all parabens were associated with ORs of 1.46 (95% CI = 0.96-2.23) and 1.32 (95% CI = 1.02-1.71), respectively, among women with hypomethylated LINE-1. A one-ln unit increase in MPB was associated with a 25% increase in the odds of hypomethylated (vs. hypermethylated) CCND2 promoter-defined BC (ROR = 1.25, 95% CI = 1.06-1.48), and a one-quantile increase in all parabens was associated with a 55% increase in the odds of hypomethylated (vs. hypermethylated) CCND2 promoter-defined BC (ROR = 1.55, 95% CI = 1.04-2.32). Exposure to parabens may increase the risk of BC among women with hypomethylated global DNAm and may increase the risk of tumors with gene-specific hypomethylated promoter regions.
对羟基苯甲酸酯是一组烷基酯，添加到消费品中以防止有害细菌和霉菌的生长。对羟基苯甲酸酯被假设会增加乳腺癌 (BC) 的风险；然而，没有研究检查过对羟基苯甲酸酯、全球 DNA 甲基化 (DNAm) 和 BC 风险之间的相互作用。我们研究了 DNAm 对对羟基苯甲酸酯与 BC 之间关联的修饰作用，以及对羟基苯甲酸酯是否与肿瘤促进剂甲基化状态定义的 BC 相关。参与者包括长岛乳腺癌研究项目中的 708 例病例和 598 例对照。在点尿样中测量了甲基对羟基苯甲酸酯 (MPB)、丙基对羟基苯甲酸酯和丁基对羟基苯甲酸酯的水平。通过长散布元件-1 (LINE-1) 和发光甲基化测定法 (LUMA) 分析测量了全球 DNAm。在 509 例病例的肿瘤样本中测量了 13 个基因的启动子甲基化状态。我们使用逻辑回归估计了 LINE-1/LUMA 分层和基因特异性启动子甲基化定义的 BC 分层中对羟基苯甲酸酯与 BC 之间关联的比值比 (OR) 和 95%置信区间 (CI)。使用比值比 (ROR) 评估了结局异质性。我们使用分位数 g 计算评估了多种对羟基苯甲酸酯的联合效应。MPB 的最高与最低三分位和所有对羟基苯甲酸酯的一个四分位数增加与低甲基化 LINE-1 女性中的 OR 分别为 1.46(95%CI=0.96-2.23)和 1.32(95%CI=1.02-1.71)相关。MPB 增加一个 ln 单位与 CCND2 启动子定义的低甲基化 (与高甲基化相比) BC 的几率增加 25%(ROR=1.25，95%CI=1.06-1.48)，所有对羟基苯甲酸酯的一个四分位数增加与 CCND2 启动子定义的低甲基化 (与高甲基化相比) BC 的几率增加 55%(ROR=1.55，95%CI=1.04-2.32)相关。暴露于对羟基苯甲酸酯可能会增加低甲基化全球 DNAm 女性的 BC 风险，并且可能会增加具有基因特异性低甲基化启动子区域的肿瘤的风险。
