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Intramural Papers of the Month

By Eddy Ball
September 2007

Acquired Tolerance to Inorganic Arsenic

In an NIEHS-funded study published in Toxicological Sciences, scientists from NIEHS and Dartmouth College reported novel insights into the mechanisms that convey acquired tolerance to inorganic arsenic in killifish - a model species with renal xenobiotic transport mechanisms similar to those found in higher vertebrates including man.

Killifish were collected from a creek near Bar Harbor, Maine, and kept in aquaria at the Mount Desert Island Biological Laboratory where they were exposed to sub-lethal levels of arsenic. Controls were kept in seawater alone. The researchers measured the effects of arsenic exposure on renal tubular expression (mRNA and protein) and transport function of multidrug resistance-associated protein 2 (Mrp2). They also measured tissue arsenic levels and evaluated mitochondrial function in tubules as an indicator of toxicity.

Although arsenic stimulation of MRP2 expression in liver and renal cell lines has been described previously, this study was the first to investigate the effects on MRP2 expression and function in vivo in intact renal proximal tubes at environmentally relevant levels of exposure. The researchers found an increase in MRP2 abundance and transport activity likely due to posttranslational processes. They proposed that up-regulation of MRP2 expression and activity was partly responsible for the tolerance to acute arsenic toxicity the fish developed. "These data have important implications for effects of arsenic on xenobiotic excretion and bioavailability," they concluded.

Citation: Miller DS, Shaw JR, Stanton CR, Barnaby R, Karlson KH, Hamilton JW, Stanton BA ( Exit NIEHS Website. 2007. MRP2 and acquired tolerance to inorganic arsenic in the kidney of killifish (Fundulus heteroclitus). Toxicol Sci 97(1):103-110.

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Chronic Bronchitis and Non-Smoking Farm Women

Using data from the Agricultural Health Study, a large, prospective study of Iowa and North Carolina pesticide applicators and their spouses, researchers found an association between agricultural risk factors and chronic bronchitis among non-smoking farm women. The study, funded jointly by NIEHS and the National Cancer Institute, was published in the Journal of Occupational and Environmental Medicine.

Researchers examined enrollment data provided by 21,541 non-smoking female spouses. The researchers analyzed current farm activities, lifetime non-farm job history and lifetime pesticide history. Not only was chronic bronchitis associated with common farm exposures (manure, driving combines, and organic dusts), but more importantly, the study was the first to demonstrate an association with pesticides. The team found at least a 50% increase in chronic bronchitis associated with the pesticides dicholorvos, DDT, cyanazine, paraquat and methyl bromide.

The cross-sectional analysis was the first to investigate pesticide use and chronic bronchitis in farm women. It was one of the only studies with sufficient power to study non-smokers alone and the largest such study to date. The research team concluded, "Our results suggest that farm women have similar risk factors as men and that some specific pesticides may also be associated with chronic bronchitis."

Citation: Valcin M, Henneberger PK, Kullman GJ, Umbach DM, London SJ, Alavanja MC, Sandler DP, Hoppin JA ( Exit NIEHS Website. 2007. Chronic bronchitis among nonsmoking farm women in the agricultural health study. J Occup Environ Med 49(5):574-583.

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Novel Genes and Pathways in Cadmium Toxicity

In an NIEHS/NTP-funded study of gene expression following exposure of C. elegans to cadmium, a team of scientists reported the discovery of novel genes and functional protein interacting networks associated with cadmium exposure. The results were published in Genome Biology by the research team of scientists from NIEHS, the National Heart, Lung and Blood Institute and Duke University.

The researchers used whole genome C. elegans DNA microarrays to monitor global changes in the nematode transcription following cadmium exposure at 4 and 24 hours. They mapped a total of 290 genes that were up-regulated and down-regulated after exposure and calculated fold changes in expression of each. They performed functional analysis of cadmium-responsive genes using RNA interference to investigate the biological consequences of changes in gene expression.

This study is important for its identification of gene families that have not been well-characterized in regard to cadmium exposure using alternative toxicological testing methods and protein-interaction analysis. The researchers also identified six novel pathways, one of which they studied in detail. "Because more than 60% of C. elegans genes and many signaling pathways are evolutionarily conserved," they concluded, "these results contribute to understanding of functional roles of various genes in cadmium related diseases in humans."

Citation: Cui Y, McBride SJ, Boyd WA, Alper S, Freedman JH ( Exit NIEHS Website. 2007. Toxicogenomic analysis of Caenorhabditis elegans reveals novel genes and pathways involved in the resistance to cadmium toxicity. Genome Biol 8(6):R122 [Epub ahead of print (DOI:10.1186/gb-2007/8/6/R122)].

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DNA Polymerase Epsilon and Leading-Strand DNA Replication

Researchers from the NIEHS Laboratory of Molecular Genetics and Laboratory of Structural Biology, in collaboration with scientists from Sweden's Umeå University, have reported findings that add significantly to understanding the roles of polymerase proteins in the process of DNA replication. In a careful examination of replication error patterns, published in the journal Science, the researchers presented a series of observations to support the inference that yeast polymerase epsilon (pol ε) participates preferentially in leading-strand DNA replication.

The researchers reached that conclusion after conducting experiments to create mistakes in replication in the yeast Saccharomyces cerevisiae using a strain containing a mutation in POL2, the gene that transcribes pol ε. The resulting mutant DNA polymerase, known as M644G pol ε, offered insight into the process due to its ability to retain replication activity and grow at rate similar to wild-type, while generating a distinct mutational signature in vivo. They observed the mutants's behavior in replicative mutagenesis triggered at different base pair locations and orientations.

This research is especially important because it provides evidence about the identity of the polymerase(s) that replicates the leading strand during the chain elongation phase of replication, something which had remained unclear for over fifty years.

Citation: Pursell ZF, Isoz I, Lundstrom EB, Johansson E, Kunkel TA ( Exit NIEHS Website. 2007. Yeast DNA polymerase epsilon participates in leading-strand DNA replication. Science 317(5834):127-130.

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