Time course of arsenic species in the brain and liver of mice after oral administration of arsenate.

The understanding of the biomethylation process of arsenic is essential to uncover the mechanisms of arsenic toxicity. This work analyzes the time course of arsenic species in the brain and liver of adult mice, after a single oral administration of three arsenate doses [2.5, 5.0 and 10 mg As(V)/kg]. Quantification of arsenic species was performed by means of liquid chromatography coupled to atomic fluorescence 2, 5, 8, 12 and 24 h after administration. The results show that 2 h after arsenate administration inorganic arsenic arrives to the liver and its concentration diminishes gradually until becoming non-detectable at 12 h. Arsenic takes longer to appear in the brain and it is present only as dimethyl arsinic acid. Since arsenic concentration decreases in liver while it increases in the brain, this suggests that the arsenic metabolite reaches the brain after formation in the liver. Importantly, the fact that dimethyl arsinic acid is no longer present after 24 h suggests the existence of a mechanism to clear this metabolite from brain tissue.

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.

Decreased nitric oxide production in the rat brain after chronic arsenic exposure.

Chronic arsenic exposure is associated with nervous system damage, vascular disease, hepatic and renal damage as well as different types of cancer. Alterations of nitric oxide (NO) in the periphery have been detected after arsenic exposure, and we explored here NO production in the brain. Female Wistar rats were exposed to arsenite in drinking water (4-5 mg/kg/day) from gestation, lactation and until 4 months of age. NOS activity, NO metabolites content, reactive oxygen species production (ROS) and lipid peroxidation (LPx) were determined in vitro in the striatum, and NO production was estimated in vivo measuring citrulline by microdialysis. Exposed animals showed a significantly lower response to NMDA receptor stimulation, reduction of NOS activity and decreased levels of nitrites and nitrates in striatum. These markers of NO function were accompanied by significantly higher levels of LPx and ROS production. These results provide evidence of NO dysfunction in the rat brain associated with arsenic exposure.

Levels of dichlorodiphenyltrichloroethane and deltamethrin in humans and environmental samples in malarious areas of Mexico.

Mexico used dichlorodiphenyltrichloroethane (DDT) to control malaria until 1999, when it was replaced with deltamethrin for mosquito control. Thus, we performed environmental and exposure assessments to DDT and deltamethrin in the states of Chiapas and Oaxaca. In Chiapas, samples were obtained at the time when DDT was being used in the malaria control program, while in Oaxaca, samples were collected 2 years after the final spraying of DDT and 2 days after deltamethrin application. Mean concentrations of DDT and Dichlorodiphenyldichloroethylene (DDE), as measured in whole blood, were 67.8 and 86.7 microg/L for children living in Chiapas and 27.1 and 60.8 microg/L for adults, respectively. As expected, DDT levels were lower 2 years after the final application in Oaxaca (20.4 and 13.2 microg/L for children and adults, respectively). Sprayers in Chiapas had the highest levels of exposure, with 165.5 and 188.4 microg/L of DDT and DDE, respectively. Women living in Chiapas and Oaxaca also had significantly higher blood levels of DDT and DDE than those women living in areas where less DDT had been used. Deltamethrin exposure was assessed only in children living in Oaxaca; 50% of the exposed group had urinary levels of 3-phenoxybenzoic acid above the limit of detection (LOD) and 6% had levels above 25 microg/L (five times the LOD), with a negative trend with age (r=-0.33). In Chiapas we found higher DDT and DDE levels in soil than in Oaxaca. In the latter location, large amounts of DDT and DDE were found in sediment samples and deltamethrin was detected in indoor soil samples. Considering the environmental data, the blood level results can be explained by soil/dust ingestion, human milk ingestion, and consumption of fish and other contaminated foods.

Fluoride-induced disruption of reproductive hormones in men.

Fluoride-induced reproductive effects have been reported in experimental models and in humans. However, these effects were found in heavily exposed scenarios. Therefore, in this work our objective was to study reproductive parameters in a population exposed to fluoride at doses of 3-27 mg/day (high-fluoride-exposed group-HFEG). Urinary fluoride levels, semen parameters, and reproductive hormones in serum (LH, FSH, estradiol, prolactin, inhibin-B, free and total testosterone) were measured. Results were compared with a group of individuals exposed to fluoride at lower doses: 2-13 mg/day (low-fluoride-exposed group-LFEG). A significant increase in FSH (P<0.05) and a reduction of inhibin-B, free testosterone, and prolactin in serum (P<0.05) were noticed in the HFEG. When HFEG was compared to LFEG, a decreased sensitivity was found in the FSH response to inhibin-B (P<0.05). A significant negative partial correlation was observed between urinary fluoride and serum levels of inhibin-B (r=-0.333, P=0.028) in LFEG. Furthermore, a significant partial correlation was observed between a chronic exposure index for fluoride and the serum concentrations of inhibin-B (r=-0.163, P=0.037) in HFEG. No abnormalities were found in the semen parameters studied in the present work, neither in the HFEG, nor in the LFEG. The results obtained indicate that a fluoride exposure of 3-27 mg/day induces a subclinical reproductive effect that can be explained by a fluoride-induced toxic effect in both Sertoli cells and gonadotrophs.