Amyotrophic Lateral Sclerosis Risk, Family Income, and Fish Consumption Estimates of Mercury and Omega-3 PUFAs in the United States.

Most amyotrophic lateral sclerosis (ALS) cases are considered sporadic, without a known genetic basis, and lifestyle factors are suspected to play an etiologic role. We previously observed increased risk of ALS associated with high nail mercury levels as an exposure biomarker and thus hypothesized that mercury exposure via fish consumption patterns increases ALS risk. Lifestyle surveys were obtained from ALS patients (n = 165) and n = 330 age- and sex-matched controls without ALS enrolled in New Hampshire, Vermont, or Ohio, USA. We estimated their annual intake of mercury and omega-3 polyunsaturated fatty acid (PUFA) via self-reported seafood consumption habits, including species and frequency. In our multivariable model, family income showed a significant positive association with ALS risk (p = 0.0003, adjusted for age, sex, family history, education, and race). Neither the estimated annual mercury nor omega-3 PUFA intakes via seafood were associated with ALS risk. ALS incidence is associated with socioeconomic status; however, consistent with a prior international study, this relationship is not linked to mercury intake estimated via fish or seafood consumption patterns.

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Selenium and risk of bladder cancer: a population-based case-control study.

Emerging evidence indicates a potential role of selenium in the prevention of several types of cancer, including bladder cancer. We investigated the association between toenail selenium concentrations and bladder cancer risk in a population-based case-control study in New Hampshire. We analyzed data from 857 incidence cases diagnosed between July 1, 1994 and June 30, 2001 and 1,191 general population controls. Newly diagnosed cases of bladder cancer were identified from the New Hampshire State Cancer Registry, which operates a rapid reporting system. Controls were selected from population lists (driver's license and Medicare enrollment). We used logistic regression analyses to generate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, and pack-years of smoking and conducted separate analyses according to the intensity of p53 immunohistochemical staining of the tumor. Overall, toenail selenium concentrations were not significantly related to bladder cancer [OR Q4 versus Q1, 0.90 (95% CI, 0.68-1.19); P(trend) = 0.15]. However, within specific subgroups there were inverse associations, i.e., among moderate smokers [OR, 0.61 (95% CI, 0.39-0.96); P(trend) = 0.004], women [OR, 0.66 (95% CI, 0.40-1.10); P(trend) = 0.11], and those with p53-positive cancers [OR Q4 versus Q1, 0.57 (95% CI, 0.34-0.94); P(trend) = 0.01]. Our results indicate that selenium is not inversely related to risk of bladder cancer overall; however, they raise the possibility that selenium may be preventive in certain molecular phenotypes of tumors (e.g., p53 positive) or within certain subsets of a population (e.g., women or moderate smokers).

Lung cancer in a U.S. population with low to moderate arsenic exposure.

BACKGROUND: Little is known about the carcinogenic potential of arsenic in areas with low to moderate concentrations of arsenic (< 100 microg/L) in drinking water. OBJECTIVES: We examined associations between arsenic and lung cancer. METHODS: A population-based case-control study of primary incident lung cancer was conducted in 10 counties in two U.S. states, New Hampshire and Vermont. The study included 223 lung cancer cases and 238 controls, each of whom provided toenail clippings for arsenic exposure measurement by inductively coupled-plasma mass spectrometry. We estimated odds ratios (ORs) of the association between arsenic exposure and lung cancer using unconditional logistic regression with adjustment for potential confounders (age, sex, race/ethnicity, smoking pack-years, education, body mass index, fish servings per week, and toenail selenium level). RESULTS: Arsenic exposure was associated with small-cell and squamous-cell carcinoma of the lung [OR = 2.75; 95% confidence interval (CI), 1.00-7.57] for toenail arsenic concentration > or = 0.114 microg/g, versus < 0.05 microg/g. A history of lung disease (bronchitis, chronic obstructive pulmonary disease, or fibrosis) was positively associated with lung cancer (OR = 2.86; 95% CI, 1.39-5.91). We also observed an elevated risk of lung cancer among participants with a history of lung disease and toenail arsenic > or = 0.05 microg/g (OR = 4.78; 95% CI, 1.87-12.2) than among individuals with low toenail arsenic and no history of lung disease. CONCLUSION: Although this study supports the possibility of an increased risk of specific lung cancer histologic types at lower levels of arsenic exposure, we recommend large-scale population-based studies.

Genomic and proteomic profiling of responses to toxic metals in human lung cells.

Examining global effects of toxic metals on gene expression can be useful for elucidating patterns of biological response, discovering underlying mechanisms of toxicity, and identifying candidate metal-specific genetic markers of exposure and response. Using a 1,200 gene nylon array, we examined changes in gene expression following low-dose, acute exposures of cadmium, chromium, arsenic, nickel, or mitomycin C (MMC) in BEAS-2B human bronchial epithelial cells. Total RNA was isolated from cells exposed to 3 M Cd(II) (as cadmium chloride), 10 M Cr(VI) (as sodium dichromate), 3 g/cm2 Ni(II) (as nickel subsulfide), 5 M or 50 M As(III) (as sodium arsenite), or 1 M MMC for 4 hr. Expression changes were verified at the protein level for several genes. Only a small subset of genes was differentially expressed in response to each agent: Cd, Cr, Ni, As (5 M), As (50 M), and MMC each differentially altered the expression of 25, 44, 31, 110, 65, and 16 individual genes, respectively. Few genes were commonly expressed among the various treatments. Only one gene was altered in response to all four metals (hsp90), and no gene overlapped among all five treatments. We also compared low-dose (5 M, noncytotoxic) and high-dose (50 M, cytotoxic) arsenic treatments, which surprisingly, affected expression of almost completely nonoverlapping subsets of genes, suggesting a threshold switch from a survival-based biological response at low doses to a death response at high doses.