作为较大案例研究的一部分,对邻苯二甲酸二丁酯(DBP)和男性生殖发育影响的毒性基因组数据集进行了评估,以测试将基因组数据纳入风险评估的方法。DBP毒理基因组数据集由来自已发表文献的九项体内研究组成,这些研究在妊娠期间将大鼠暴露于DBP,并评估了雄性胎儿的睾丸或沃尔夫导管中的基因表达变化。这项工作侧重于定性评估,基于缺乏可用的剂量反应数据,DBP毒理基因组数据集,以假设男性生殖发育结果的作用模式和机制,发生在较低的剂量范围内。在基因和途径水平上对大鼠睾丸的8项DBP毒理基因组学研究进行了证据权重评估。结果表明,DBP诱导类固醇生成途径和脂质/甾醇/胆固醇转运途径中的基因下调,以及对早期基因/生长/分化的影响,转录,过氧化物酶体增殖物激活受体信号和睾丸中的凋亡途径。由于两种既定的行动模式(MOA),降低胎儿睾丸睾酮产生和Insl3基因表达,解释子宫内DBP暴露后在大鼠中观察到的一些但不是全部的睾丸效应,其他MOA可能会有效。对一项DBP微阵列研究的重新分析确定了细胞信号传导中的其他途径,新陈代谢,激素,疾病,和细胞粘附的生物过程。这些推测的新通路可能与DBP对睾丸的影响有关,目前无法解释。这个关于DBP的案例研究确定了在风险评估中使用毒物基因组数据的数据空白和研究需求。此外,这项研究展示了一种在人类健康风险评估中评估毒物基因组数据的方法,该方法可应用于未来的化学品.
An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger
case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose-response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This
case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals.