Methyl group balance in brain and liver: role of choline on increased S-adenosyl methionine (SAM) demand by chronic arsenic exposure.

Arsenic toxicity has been related to its interference with one carbon metabolism, where a high demand of S-adenosylmethionine (SAM) for arsenic methylation as well as a failure of its regeneration would compromise the availability of methyl groups for diverse cellular functions. Since exposed animals show disturbances of methylated products such as methylated arginines, myelin and axon membranes, this work investigates whether alterations of SAM, choline and phosphatidylcholine (PC) in the brain of arsenic exposed rats are associated with myelin alterations and myelin basic protein (MBP) immunoreactivity. Also these metabolites, morphologic and biochemical markers of methyl group alterations were analyzed in the liver, the main site of arsenic methylation. In adult, life-long arsenic exposed rats through drinking water (3 ppm), no changes of SAM, choline and PC concentrations where found in the brain, but SAM and PC were severely decreased in liver accompanied by a significant increase of choline. These results suggest that choline plays an important role as methyl donor in arsenic exposure, which could underlie hepatic affections observed when arsenic exposure is combined with other environmental factors. Also, important myelin and nerve fiber alterations, accompanied by a 75% decrease of MBP immunoreactivity were not associated with a SAM deficit in the brain.

Decreased arginine methylation and myelin alterations in arsenic exposed rats.

Methylation has an important role in the synthesis of myelin basic protein (MBP), an essential component that confers compactness to myelin, and the correct synthesis and assembling of myelin are fundamental in the development of the central nervous system. Since arsenic metabolism requires a high consumption of S-adenosylmethionine, the main donor of methyl groups in the organism, it has been proposed that arsenic exposure can lead to a demethylation status in the organism comprising DNA and protein hypomethylation. This study documents myelin alterations in brain and changes in levels of methylated arginines in brain and serum of adult female Wistar rats exposed to arsenic (3 and 36 ppm, drinking water) from gestation throughout lactation, development and until 1, 2, 3 and 4 months of age. Morphological characteristics were analyzed by means of light microscopy and methylated arginines were analyzed through HPLC. Arsenic intake resulted in myelin damage reflected as empty spaces in fiber tracts of the exposed animals. The low exposure group (approximately 0.4 mg/kg/day) did not present myelin damage during the first 2 months, only moderate alterations in the third and fourth months. By contrast, animals exposed to 36 ppm (approximately 4 mg/kg/day) showed moderate to severe damage to nerve tracts from the first month of age. These alterations were accompanied by significant lower levels of dimethyl arginine in both exposed groups, as compared with the controls, in the third and fourth months of age and exposure. These data demonstrate that myelin composition is a target of arsenic through interference with arginine methylation, and they suggest that disturbances in nervous transmission through myelinated fibers are an important component of arsenic neurotoxicity.