BACKGROUND There is a suite of chemicals, including metals, pesticides, and personal care product compounds, which are commonly detected at high levels in US Center for Disease Control's National Health and Nutrition Examination Survey (NHANES) chemical biomarker screens. Whether these chemicals influence development of breast cancer is not well understood. OBJECTIVES The objectives were to perform an unbiased concentration-dependent assessment of these chemicals, to quantify differences in cancer-specific genes and pathways, to describe if these differences occur at human population-relevant concentrations, and to specifically test for differences in markers of stemness and cellular plasticity. METHODS We treated nontumorigenic mammary epithelial cells, MCF10A, with 21 chemicals at four concentrations (25 nM, 250 nM, 2.5μM, and 25μM) for 48 h. We conducted RNA-sequencing for these 408 samples, adapting the plexWell plate-based RNA-sequencing method to analyze differences in gene expression. We calculated gene and biological pathway-specific benchmark concentrations (BMCs) using BMDExpress3, identifying differentially expressed genes and generating the best fit benchmark concentration models for each chemical across all genes. We identified enriched biological processes and pathways for each chemical and tested whether chemical exposures change predicted cell type distributions. We contextualized benchmark concentrations relative to human population biomarker concentrations in NHANES. RESULTS We detected chemical concentration-dependent differences in gene expression for thousands of genes. Enrichment and cell type distribution analyses showed benchmark concentration responses correlated with differences in breast cancer-related pathways, including induction of basal-like characteristics for some chemicals, including arsenic, lead, copper, and methyl paraben. Comparison of benchmark data to NHANES chemical biomarker (urine or blood) concentrations indicated an overlap between exposure levels and levels sufficient to cause a gene expression response. DISCUSSION These analyses revealed that many of these 21 chemicals resulted in differences in genes and pathways involved in breast cancer in vitro at human exposure-relevant concentrations. https://doi.org/10.1289/EHP12886.

中文翻译：

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暴露于环境相关化学品的非致瘤性乳腺细胞的高通量转录组学。


背景技术有一系列化学物质，包括金属、杀虫剂和个人护理产品化合物，在美国疾病控制中心的国家健康和营养检查调查(NHANES)化学生物标志物筛查中通常检测到高含量的化学物质。这些化学物质是否影响乳腺癌的发展尚不清楚。目的 目的是对这些化学物质进行无偏倚的浓度依赖性评估，量化癌症特异性基因和途径的差异，描述这些差异是否发生在与人群相关的浓度下，并专门测试干性标记的差异和细胞可塑性。方法 我们用四种浓度（25 nM、250 nM、2.5μM 和 25μM）的 21 种化学物质处理非致瘤性乳腺上皮细胞 MCF10A 48 小时。我们对这 408 个样本进行了 RNA 测序，采用基于 plexWell 板的 RNA 测序方法来分析基因表达的差异。我们使用 BMDExpress3 计算了基因和生物途径特定的基准浓度 (BMC)，识别差异表达的基因，并为所有基因中的每种化学物质生成最适合的基准浓度模型。我们确定了每种化学物质的丰富生物过程和途径，并测试化学物质暴露是否会改变预测的细胞类型分布。我们将基准浓度与 NHANES 中的人群生物标志物浓度联系起来。结果我们检测到数千个基因的基因表达存在化学浓度依赖性差异。 富集和细胞类型分布分析显示基准浓度反应与乳腺癌相关途径的差异相关，包括诱导某些化学物质的基础样特征，包括砷、铅、铜和对羟基苯甲酸甲酯。基准数据与 NHANES 化学生物标志物（尿液或血液）浓度的比较表明暴露水平和足以引起基因表达反应的水平之间存在重叠。讨论 这些分析表明，这 21 种化学物质中的许多在人体暴露相关浓度下会导致体外乳腺癌相关基因和通路的差异。 https://doi.org/10.1289/EHP12886。