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Arsenic Metabolism and Distribution in Developing Organisms
Citation:
THOMAS, D. J. Arsenic Metabolism and Distribution in Developing Organisms. Presented at 2009 Annual Society of Toxicology Meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This abstract describes the factors affecting the distribution and retention of inorganic arsenic and its methylated metabolites in developing mice. The metabolic factors affecting the ontogeny of methylation processes and membrane transport processes are considered as they relate to the long term consequences of exposure to inorganic arsenic in early life.
Description:
A growing body of evidence suggests that exposure to inorganic arsenic during early life has long term adverse effects. The extent of exposure to inorganic arsenic and its methylated metabolites in utero is determined not only by the rates of formation and transfer of arsenicals across the placenta but also by ontogeny of arsenic metabolism in the developing organism. For example, in a mouse model for transplacental carcinogenesis of inorganic arsenic, fetuses at gestational day 18 contain inorganic, methylated, and dimethylated arsenic in placenta, liver, lung, and blood. The methylated arsenicals in fetal tissues could be transferred from the mother or formed in situ. Because concentrations of these arsenicals in fetal tissues were lower than those found in corresponding maternal tissues, there is likely a placental barrier to the transfer of arsenicals from mother to fetus or a maternal-fetal difference in the uptake, production, or retention of these arsenicals. Arsenic (+3 oxidation state) methyltransferase which catalyzes the formation of methylated arsenicals is detectable in fetal tissues by mid-gestation. However, it is unknown whether the protein is catalytically active in utero. For example, the activity of arsenic (+3 oxidation state) methyltransferase is dependent on the presence of dithiol reductants (thioredoxin, glutaredoxin) and is modulated by glutathione. Availability of these factors during development may control the ontogeny of the activity of arsenic (+3 oxidation state) methyltransferase and may affect the levels of methylated arsenicals found in fetal tissues. In addition, developmental changes in the levels of transporters that mediate the uptake and loss of arsenicals from cells could affect accumulation in fetal tissues. Elucidating the roles of transport and metabolism in the kinetic behavior of inorganic arsenic in fetal tissues could contribute to understanding genetic and epigenetic consequences of early life exposure to this metalloid. (This abstract does not reflect US EPA policy.)