Developmentally Restricted Genetic Determinants of Human Arsenic Metabolism: Association between Urinary Methylated Arsenic and CYT19 Polymorphisms in Children

Abstract

We report the results of a screen for genetic association with urinary arsenic metabolite levels in three arsenic metabolism candidate genes, PNP, GSTO, and CYT19, in 135 arsenic-exposed subjects from the Yaqui Valley in Sonora, Mexico, who were exposed to drinking water concentrations ranging from 5.5 to 43.3 ppb. We chose 23 polymorphic sites to test in the arsenic-exposed population. Initial phenotypes evaluated included the ratio of urinary inorganic arsenic(III) to inorganic arsenic(V) and the ratio of urinary dimethylarsenic(V) to monomethylarsenic(V) (D:M). In the initial association screening, three polymorphic sites in the CYT19 gene were significantly associated with D:M ratios in the total population. Subsequent analysis of this association revealed that the association signal for the entire population was actually caused by an extremely strong association in only the children (7–11 years of age) between CYT19 genotype and D:M levels. With children removed from the analysis, no significant genetic association was observed in adults (18–79 years). The existence of a strong, developmentally regulated genetic association between CYT19 and arsenic metabolism carries import for both arsenic pharmacogenetics and arsenic toxicology, as well as for public health and governmental regulatory officials.

Low 8-oxo-7,8-dihydro-2′-deoxyguanosine levels and influence of genetic background in an Andean population exposed to high levels of arsenic

“…The variation in As metabolite pattern is partly due to genetic polymorphisms, especially in As(+III)methyltransferase (AS3MT) [22][23][24][25][26][27]. Other polymorphisms that may 4 influence the 8-OxodG levels include genes involved in ROS detoxification and resistance.…”

Biologically based modeling of multimedia, multipathway, multiroute population exposures to arsenic

“…However, (a) chemical form and bioavailability of As in environmental and microenvironmental media, including food (USEPA, 1998), (b) routes and pathways of exposure Zartarian et al, 2006), (c) presence of other contaminants (Hays et al, 2006), and (d) individual variability in metabolism, depending on genetic makeup and developmental stage (Meza et al, 2005;Suzuki, 2005;Valenzuela et al, 2005) are important in determining biologically relevant target tissue dose and health effects.…”

Role of Arsenic (+3 Oxidation State) Methyltransferase in Arsenic Metabolism and Toxicity

“…36) To understand the relationship between genetic variants of As3MT and arsenic metabolism, Meza et al examined the associations of the urinary arsenic metabolites with 23 types of polymorphisms of the genes involved in arsenic metabolism such as GSTO, PNP, and As3MT among the arsenic-exposed subjects living in the Yaqui Valley of Sonora, Mexico. 37) The results showed that the ratio of urinary DMA/MMA in the children (7-11 years of age) were significantly associated with three intronic polymorphisms in As3MT (rs12767543, rs3740393, and rs11191453), but not with the polymorphisms in GSTO and PNP genes. Schläwicke Engström et al 38) tested the associations of the polymorphisms in the As3MT gene with urinary arsenic metabolites among women living in San Antonio de los Cobres, a village in the northern Argentinean Andes.…”