National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC, USA.
Toxicol Appl Pharmacol. 2013 Sep 15;271(3):349-62. doi: 10.1016/j.taap.2011.06.014. Epub 2011 Jun 30.
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.
作为更大案例研究的一部分，对邻苯二甲酸二丁酯 (DBP) 的毒理基因组数据集和男性生殖发育效应进行了评估，旨在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使大鼠暴露于 DBP，并评估雄性胎儿睾丸或沃尔夫管中的基因表达变化。该研究主要基于缺乏可用剂量-反应数据，对 DBP 毒理基因组数据集进行定性评估，以推测男性生殖发育结果的作用模式和机制，这些结果发生在较低剂量范围内。对大鼠睾丸的八项 DBP 毒理基因组研究进行了基因和途径水平的证据权重评估。结果表明，DBP 诱导类固醇生成途径和脂质/固醇/胆固醇转运途径中的基因下调以及对睾丸中即时早期基因/生长/分化、转录、过氧化物酶体增殖物激活受体信号和细胞凋亡途径的影响具有较强的证据。由于两种已确立的作用模式（MOA），即胎儿睾丸睾酮产生减少和 Insl3 基因表达减少，可以解释大鼠宫内 DBP 暴露后观察到的一些但不是全部睾丸效应，因此其他 MOA 可能起作用。对一项 DBP 微阵列研究的重新分析确定了细胞信号转导、代谢、激素、疾病和细胞黏附生物学过程中的其他途径。这些假定的新途径可能与 DBP 对睾丸的影响有关，目前这些影响尚无法解释。该 DBP 案例研究确定了在风险评估中使用毒理基因组数据的差距和研究需求。此外，本研究展示了一种可应用于未来化学物质的人类健康风险评估中评估毒理基因组数据的方法。
