Dreiem Anne, Rykken Sidsel, Lehmler Hans-Joachim, Robertson Larry W, Fonnum Frode
Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Toxicol Appl Pharmacol. 2009 Oct 15;240(2):306-13. doi: 10.1016/j.taap.2009.07.016. Epub 2009 Jul 22.
Polychlorinated biphenyls (PCBs) are persistent organic pollutants that bioaccumulate in the body, however, they can be metabolized to more water-soluble products. Although they are more readily excreted than the parent compounds, some of the metabolites are still hydrophobic and may be more available to target tissues, such as the brain. They can also cross the placenta and reach a developing foetus. Much less is known about the toxicity of PCB metabolites than about the parent compounds. In the present study, we have investigated the effects of eight hydroxylated (OH) PCB congeners (2'-OH PCB 3, 4-OH PCB 14, 4-OH PCB 34, 4'-OH PCB 35, 4-OH PCB 36, 4'-OH PCB 36, 4-OH PCB 39, and 4'-OH PCB 68) on reactive oxygen species (ROS) formation and cell viability in rat cerebellar granule cells. We found that, similar to their parent compounds, OH-PCBs are potent ROS inducers with potency 4-OH PCB 14<4-OH PCB 36<4-OH PCB 34<4'-OH PCB 36<4'-OH PCB 68<4-OH PCB 39<4'-OH PCB 35. 4-OH PCB 36 was the most potent cell death inducer, and caused apoptotic or necrotic morphology depending on concentration. Inhibition of ERK1/2 kinase with U0126 reduced both cell death and ROS formation, suggesting that ERK1/2 activation is involved in OH-PCB toxicity. The results indicate that the hydroxylation of PCBs may not constitute a detoxification reaction. Since OH-PCBs like their parent compounds are retained in the body and may be more widely distributed to sensitive tissues, it is important that not only the levels of the parent compounds but also the levels of their metabolites are taken into account during risk assessment of PCBs and related compounds.
多氯联苯（PCBs）是持久性有机污染物，会在体内生物累积，不过，它们可代谢为水溶性更强的产物。尽管这些代谢产物比母体化合物更容易排出体外，但其中一些仍然具有疏水性，可能更容易作用于靶组织，如大脑。它们还能穿过胎盘并影响发育中的胎儿。与母体化合物相比，人们对多氯联苯代谢产物的毒性了解要少得多。在本研究中，我们研究了8种羟基化（OH）多氯联苯同系物（2'-OH PCB 3、4-OH PCB 14、4-OH PCB 34、4'-OH PCB 35、4-OH PCB 36、4'-OH PCB 36、4-OH PCB 39和4'-OH PCB 68）对大鼠小脑颗粒细胞中活性氧（ROS）生成及细胞活力的影响。我们发现，与它们的母体化合物类似，羟基化多氯联苯是强效的ROS诱导剂，其诱导能力顺序为4-OH PCB 14＜4-OH PCB 36＜4-OH PCB 34＜4'-OH PCB 36＜4'-OH PCB 68＜4-OH PCB 39＜4'-OH PCB 35。4-OH PCB 36是最有效的细胞死亡诱导剂，根据浓度不同会导致细胞出现凋亡或坏死形态。用U0126抑制ERK1/2激酶可减少细胞死亡和ROS生成，这表明ERK1/2激活参与了羟基化多氯联苯的毒性作用。结果表明，多氯联苯的羟基化可能并不构成解毒反应。由于羟基化多氯联苯与其母体化合物一样会留存于体内，并且可能更广泛地分布到敏感组织中，因此在对多氯联苯及相关化合物进行风险评估时，不仅要考虑母体化合物的水平，还要考虑其代谢产物的水平，这一点很重要。
