Methylmercury-induced mitochondrial DNA synthesis in neural tissue of cats

The association between selected neuropathological lesions and effects on mitochondrial and nuclear DNA synthesis was explored in cats exposed in vivo to methylmercuric chloride. Two groups of eight adult female cats ingested 0 or 176 micrograms Hg/kg body wt/day as methylmercuric chloride added daily to their diet. Treated animals and concurrent controls were sacrificed following the onset of clinical signs of toxicity, with the mean termination time being about 12 (range 7-15) weeks. Terminal Hg levels for the control and treated groups respectively were 0.16 +/- 0.02 and 12 +/- 1 ppm in the cerebrum and 0.16 +/- 0.01 and 14 +/- 1 ppm in blood. Hydroxyurea-resistant [3H]thymidine incorporation into DNA in cultured explants of cerebrum and cerebellum, as measured by scintillation counting of extracted DNA, was elevated for treated animals. Autoradiographic analysis indicated that the excess DNA synthesis was cytoplasmic, and deoxyribonuclease resistant, suggesting a mitochondrial DNA origin. The excess DNA synthesis was pronounced in cell types prone to neurodegeneration, specifically the Purkinje cells and the granular cell layer in the cerebellum and the large neurons in the cerebrum. Mitochondrial DNA from neural tissues of an additional five pairs of cats treated for 8 weeks was isolated from cesium chloride/ethidium bromide density gradients. Thymidine incorporation into mitochondrial DNA was greater in methylmercury-treated than control animals. These observations indicate that methylmercury affects mitochondrial DNA synthesis in vivo with a tissue specificity parallel to that of neuropathological lesions.