The mechanism(s) by which arsenic exposure contributes to human cancer
risk is unknown; however, several indirect cocarcinogenesis mechanisms
have been proposed. Many studies support the role of As in altering one
or more DNA repair processes. In the present study we used individual-level
exposure data and biologic samples to investigate the effects
of As exposure on nucleotide excision repair in two study populations, focusing
on the excision repair cross-complement 1 (ERCC1) component. We
measured drinking water, urinary, or toenail As levels and obtained
cryopreserved lymphocytes of a subset of individuals enrolled in epidemiologic
studies in New Hampshire (USA) and Sonora (Mexico). Additionally, in
corroborative laboratory studies, we examined the effects of
As on DNA repair in a cultured human cell model. Arsenic exposure was
associated with decreased expression of ERCC1 in isolated lymphocytes
at the mRNA and protein levels. In addition, lymphocytes from As-exposed
individuals showed higher levels of DNA damage, as measured by a
comet assay, both at baseline and after a 2-acetoxyacetylaminofluorene (2-AAAF) challenge. In
support of the in vivo data, As exposure decreased ERCC1 mRNA expression and enhanced levels
of DNA damage after a 2-AAAF challenge in cell culture. These data provide
further evidence to support the ability of As to inhibit the DNA
repair machinery, which is likely to enhance the genotoxicity and mutagenicity
of other directly genotoxic compounds, as part of a cocarcinogenic
mechanism of action.
In this comparative study, we compensated for many of the known variables that influence children's growth and development by selecting two groups of 4-5-year-old Yaqui children who reside in the Yaqui Valley of northwestern Mexico. These children share similar genetic backgrounds, diets, water mineral contents, cultural patterns, and social behaviors. The major difference was their exposure to pesticides. Pesticides have been applied to the agricultural area of the valley since the late 1940s. In 1990, high levels of multiple pesticides were found in the cord blood of newborns and in breast milk. Building on anthropological methods for rapid rural appraisal of problems within the environment, a Rapid Assessment Tool for Preschool Children (RATPC) was developed to measure growth and development. The children of the agrarian region were compared to children living in the foothills, where pesticide use is avoided. The RATPC measured varied aspects of physical growth and abilities to perform, or function in, normal childhood activities. No differences were found in growth patterns. Functionally, the exposed children demonstrated decreases in stamina, gross and fine eye-hand coordination, 30-minute memory, and the ability to draw a person. The RATPC also pointed out areas in which more in-depth research on the toxicology of pesticides would be valuable.ImagesFigure 1Figure 2
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.
In this comparative study, wE compensated for many of the known variables that influence children's growth and development by selecting two groups of 4-5-year-old Yaqui children who reside in the Yaqui Valley of northwestern Mexico. These children share silar geneic backgrounds, diets, water mineral contents, culural patterns, and social beviors. the major difference was their exposure to pesticides. Pesticides have been applied to the agricultural area of the valley since the late 1940s-iIn 199, igh levels of multiple pesticides were found in the cord blood of newborns and in breast milk. Building on anthropologicad methods for rapid rural appraisal of problems within the environment, a Rapid Assessment Tool for Preschool Children (RATPC) was developed to measure growth and development. The children of the agrarian region were compared to children living in the foothills, where pesticide use is avoidedd The RATPC measured varied aspects ofphycal growth and abiliies t perform, or function in, normal childhood activities. No dierences were found in g patterns. Functionally, the exposed children demonstratd decreases in stanina, goss ni e eye-hand coordination, 30minute memory, and the ability' to draw a person. The RATPC a pointe out areas in which more in-depth research on toxicoogy of pesticide would b vluable. Key wrd children,
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