Perinatal Exposure to Purity-Controlled Polychlorinated Biphenyl 52, 138, or 180 Alters Toxicogenomic Profiles in Peripheral Blood of Rats after 4 Months

It is known from controlled animal experiments and human epidemiologic studies that early life exposure to mixtures of polychlorinated biphenyls (PCBs) is a risk factor for developmental neurotoxicity. The importance of non-dioxin-like PCBs in the context of the observed effect is uncertain because of the blending with the more potent dioxin-like PCBs. Previously, a controlled rat perinatal exposure study with individual, purity-controlled, non-dioxin-like congeners (PCB52, PCB138, or PCB180) was set up. Impaired motor coordination, motor activity, and learning has been reported for the offspring at an age of approximately 4 months. Here, we report on the gene expression responses that have been observed in the blood of the same animals. ANOVA analysis called 1412 genes differentially expressed 4 months after the PCB treatment was stopped. Subsequently, each PCB exposure condition was compared to the corresponding vehicle control using a fold change analysis. The gene lists contained between 82 and 348 differentially expressed genes. Expression patterns were complex with sets of differentially expressed genes being specific for a particular PCB exposure and other sets in common between several exposure conditions. Thirty-two genes were differentially expressed under all conditions. Bioinformatic overrepresentation analysis identified enriched biological terms such as lipid metabolism, molecular transport, small molecule biochemistry, and cell signaling and proliferation. Gene lists were particularly enriched for nervous system development and function ontology. In conclusion, we have documented for the first time differential gene expression in a well-controlled animal study that reported behavioral effects of purity-controlled individual non-dioxin-like PCBs.

已有对照动物实验与人类流行病学研究证实，生命早期暴露于多氯联苯（polychlorinated biphenyls，PCBs）混合物是发育性神经毒性的风险因素。但由于与活性更强的二噁英样多氯联苯混合，非二噁英样多氯联苯在上述效应中的作用尚不明确。此前已有团队开展对照大鼠围产期暴露实验，采用单一、纯度可控的非二噁英样多氯联苯同系物（PCB52、PCB138或PCB180）进行染毒。研究已报道，暴露组子代大鼠在约4月龄时出现运动协调能力、运动活性及学习能力受损。本研究针对上述同一批动物的血液样本，报道其基因表达应答特征。方差分析（Analysis of Variance，ANOVA）结果显示，在多氯联苯染毒结束4个月后，共有1412个基因呈现差异表达。随后，针对每一种多氯联苯暴露组，均通过差异倍数分析与对应溶剂对照组进行比较。各差异基因列表包含82至348个不等的差异表达基因。基因表达模式较为复杂：部分差异表达基因仅在某一种多氯联苯暴露组中特异性表达，另有部分基因在多种暴露条件下呈现共同表达特征。另有32个基因在所有暴露条件下均呈现差异表达。生物信息学富集分析结果显示，富集的生物学功能术语包括脂质代谢、分子转运、小分子生物化学过程以及细胞信号传导与增殖等。差异基因列表尤其在神经系统发育与功能相关的基因本体（Gene Ontology）条目上呈现富集。综上，本研究首次在一项严格对照的动物实验中证实，经纯度控制的单一非二噁英样多氯联苯可引发差异基因表达，且该实验已报道了此类物质的行为学效应。