Hydroxylated polychlorinated biphenyls increase reactive oxygen species formation and induce cell death in cultured cerebellar granule cells

Abstract

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.

Assessment of hydroxylated metabolites of polychlorinated biphenyls as potential xenoestrogens: a QSAR comparative analysis∗

“…OH-PCBs have also been shown to inhibit mitochondrial oxidative phosphorylation, thyroid hormone sulphation, estrogen sulfotranferase, to affect thyroxine (T4) levels, and to exhibit estrogenic or anti-estrogenic activity in mammals [3][4][5]8,9,11,16,[26][27][28][29][30][31][32]. Currently, OH-PCBs are attracting increasing attention for their potential endocrine disruption activity.…”

Accumulation and efflux of polychlorinated biphenyls in Escherichia coli

“…Unlike PCBs, which often accumulate in the adipose tissues of human and animals, HPCBs are capable of circulating with blood to reach various organs [13]. Many HPCB species have been detected in human serum samples and wildlife blood samples [14].…”

Endocrine disruptors from the environment affecting breast cancer (Review)

“…Studies (165) focused on that concept also have shown that the production of ROS after metabolic reactions of PCBs behaves in a dose-time-depend manner (165). It is well-known that PCBs act as endocrine disruptors, having an estrogenic action defined by their affinity (166). Moreover, it is known that catechol metabolites of E2 induce free radical damage and this damage was detected as DNA strand breaks and the formation of 8-oxodeoxyguanosine (8-oxodG).…”

“…Therefore, inhibition of ROCK appears to represent a novel therapeutic approach for metastases in breast cancer upon PCB exposure (169). However, it has been observed that metabolized products as hydroxylated (OH) PCB congeners, (OH)-PCB, can distribute differently to their progenitors due to their solubility, therefore, they are able to reach other organs and contribute to other processes such as altering cell cycle via ERK1/2 and contributing to neurotoxicity instead of generating only ROS (166).…”