Methylmercury (MeHg) is especially toxic to the developing central nervous system. In order to understand the reasons for this age-dependent vulnerability, we compared the effects of MeHg on formation of reactive oxygen species (ROS) and mitochondrial function in striatal synaptosomes obtained from rats of various ages. Basal ROS levels were greater, and basal mitochondrial function was lower, in synaptosomes from younger animals, compared to adult animals. MeHg induced ROS formation in synaptosomes from rats of all ages, although the increases were greatest in synaptosomes from the younger animals. MeHg also reduced mitochondrial metabolic function, as assessed by MTT reduction, as well as mitochondrial membrane potential; again, the greatest changes were seen in synaptosomes from early postnatal animals. These age-dependent differences in susceptibility to MeHg are most likely due to a less efficient ROS detoxifying system and lower activity of mitochondrial enzymes in tissue from young animals.

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.

The brain is the main target organ for methylmercury (MeHg), a highly toxic compound that bioaccumulates in aquatic systems, leading to high exposure in humans who consume large amounts of fish. The mechanisms responsible for MeHg-induced changes in neuronal function are, however, not yet fully understood. In the present study we investigated whether MeHg-induced elevations in reactive oxygen species (ROS) or intracellular calcium are responsible for altering mitochondrial metabolic function in rat striatal synaptosomes. MeHg decreased mitochondrial function (measured by the conversion of MTT to formazan) and increased ROS levels in striatal synaptosomes after 30 min exposure. Although co-incubation with the antioxidant Trolox significantly reduced MeHg-induced ROS levels, it failed to restore mitochondrial function. MeHg also increased cytosolic and mitochondrial calcium levels in striatal synaptosomes. These elevations were largely independent of extrasynaptosomal calcium, given that nominal calcium-free buffer with 20 microM EGTA did not prevent MeHg-induced increases in cytosolic calcium. In conclusion, we suggest that ROS are not the cause of mitochondrial dysfunction in striatal synaptosomes after MeHg exposure; rather, we propose that ROS formation is a downstream event that reflects MeHg-induced mitochondrial dysfunction due to increased mitochondrial calcium levels.

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