John Pierce Wise

The cytotoxicity and genotoxicity of particulate and soluble hexavalent chromium in human lung cells

Hexavalent chromium (Cr(VI)) is a human lung carcinogen. Cr(VI) is a particularly important and dangerous carcinogen, because there is widespread exposure to it both occupationally and to the general public. However, despite the potential for widespread exposure and the fact that the lung is its target organ, there are few reports of the genotoxicity of Cr(VI) in human lung cells. Clearly, in order to better understand this carcinogen, its effects in its target cells need to be evaluated. Accordingly, we determined the cytotoxicity and clastogenicity of both particulate (water-insoluble) and soluble Cr(VI) in primary human bronchial fibroblasts (PHBFs). We used lead chromate (PbCrO(4)) and sodium chromate (Na(2)CrO(4)) as prototypical particulate and soluble Cr(VI) salts, respectively. Both compounds induced concentration-dependent cytotoxicity after a 24h exposure in PHBFs. The relative survival was 87, 46, 26 and 2% after exposure to 0.1, 0.5, 1 and 5 microg/cm(2) PbCrO(4), respectively, and 74, 57, 13 and 0% after exposure to 1, 2.5, 5 and 10 microM Na(2)CrO(4), respectively. Similarly, the amount of chromosome damage increased with concentration after 24h exposure to both compounds. Specifically, 0.1, 0.5 and 1 microg/cm(2) PbCrO(4) damaged 15, 34 and 42% of metaphase cells with the total amount of damage reaching 18, 40 and 66 aberrations per 100 metaphases, respectively. PbCrO(4) (5 microg/cm(2)) induced such profound cell cycle delay that no metaphases were found. Na(2)CrO(4) (1 and 2.5 microM) damaged 18 and 33% of metaphase cells with the total amount of damage reaching 19 and 43 aberrations per 100 metaphases, respectively. Na(2)CrO(4) (5 and 10 microM) induced such profound cell cycle delay that no metaphases were found. Overall the data clearly indicate that Cr(VI) compounds are cytotoxic and genotoxic to human lung cells.

Hexavalent Chromium-Induced DNA Damage and Repair Mechanisms

Hexavalent chromium is a commonly used industrial metal that has been shown to induce lung cancer in workers having long term exposure. In the particulate form, Cr(VI) dissolves slowly in vivo, leading to an extended exposure of lung cells. Hexavalent chromium is taken into the cell and rapidly reduced to Cr(V), Cr(IV), Cr(III), and reactive oxygen species. Cells treated with Cr(VI) are subject to several types of DNA damage resulting from this reduction, including base modification, single-strand breaks, double-strand breaks, Cr-DNA adducts, DNA-Cr-DNA adducts, and protein-Cr-DNA adducts. These types of damage, if left unrepaired or are misrepaired, can lead to growth arrest, cytotoxicity, and apoptosis, as well as mutations leading to neoplastic transformation and ultimately tumorigenesis. Here we review the current literature on Cr-induced DNA damage and its repair.

Antioxidant status and hearing function in noise-exposed workers.

The cellular antioxidant system appears to protect cochlear hair cells from oxidative stress due to noise and aging. The role of individual metabolic variables remains poorly understood, however. We examined the role of a number of metabolic factors on human cochlear function in noise-exposed individuals. In 58 factory workers we measured audiometry and distortion product otoacoustic emissions prior to a workshift. Simultaneously we measured levels of vitamin E, vitamin C, and polymorphism status for two metabolic genes related to glutathione S-transferase function (GSTM1 and GSTT1). Age and total noise exposure were predictive of hearing status. Vitamin E levels were negatively correlated with hearing function, and this effect was partly explained by an increase in vitamin E levels with age. No effect was found for vitamin C. Individuals possessing the GSTM1 gene had significantly better high frequency otoacoustic emissions compared to GSTM1 null individuals. The protective effect of GSTM1 was present even after adjusting for age, race, sex, and years of noise exposure. GSTT1 did not exhibit a similarly protective effect. While the cross-sectional nature of the study precludes drawing conclusions about causation, these data suggest that GSTM1, an antioxidant enzyme which is found in the mammalian cochlea, may play a protective role in humans against hair cell damage due to noise or aging.

A global assessment of chromium pollution using sperm whales (Physeter macrocephalus) as an indicator species.

Chromium (Cr) is a well-known human carcinogen and a potential reproductive toxicant, but its contribution to ocean pollution is poorly understood. The aim of this study was to provide a global baseline for Cr as a marine pollutant using the sperm whale (Physeter macrocephalus) as an indicator species. Biopsies were collected from free-ranging whales around the globe during the voyage of the research vessel The Odyssey. Total Cr levels were measured in 361 sperm whales collected from 16 regions around the globe detectable levels ranged from 0.9 to 122.6 microg Cr g tissue(-1) with a global mean of 8.8+/-0.9 microg g(-1). Two whales had undetectable levels. The highest levels were found in sperm whales sampled in the waters near the Islands of Kiribati in the Pacific (mean=44.3+/-14.4) and the Seychelles in the Indian Ocean (mean=19.5+/-5.4 microg g(-1)). The lowest mean levels were found in whales near the Canary Islands (mean=3.7+/-0.8 microg g(-1)) and off of the coast of Sri Lanka (mean=3.3+/-0.4 microg g(-1)). The global mean Cr level in whale skin was 28-times higher than mean Cr skin levels in humans without occupational exposure. The whale levels were more similar to levels only observed previously in human lung tissue from workers who died of Cr-induced lung cancer. We conclude that Cr pollution in the marine environment is significant and that further study is urgently needed.

Glutathione S-transferase M1 and T1 genetic polymorphisms, alcohol consumption and breast cancer risk.

Alcohol consumption has been inconsistently associated with breast cancer risk. Recent studies suggest that genetic polymorphisms of glutathione S-transferases (GSTs) may modify this relation. To determine if breast cancer risk is associated with GSTM1 and GSTT1 genetic polymorphisms, and to evaluate the effect modification between GST genotypes and alcohol consumption in the risk of breast cancer, we conducted a case–control study in the state of Connecticut in the period 1998 and 2001. Cases were histologically confirmed, incident breast cancer patients in New Haven County, CT. Controls were randomly selected from women histologically confirmed to be without breast cancer. The study results show that, while GSTM1 genotypes were not associated with breast cancer risk, GSTT1-null genotype was associated with a significant 90% increased risk for postmenopausal women (OR=1.9, 95% CI 1.2–3.0). Analysis by GST genotypes and alcohol consumption shows that GSTM1A ever-drinking women had a 2.5-fold (OR=2.5, 95% CI 1.1–5.5) increased risk of breast cancer compared to the GSTM1A never-drinkers, and the risk increases with duration and daily amount of alcohol consumption. Postmenopausal women with GSTT1-null genotype, who consumed a lifetime of >250u2009kg of spirit-equivalents, had an almost seven-fold increased risk (OR=6.8, 95% CI 1.4–33.9), and drinking commencing at younger ages appears to carry a higher risk. An OR of 8.2 (95% CI 1.2–57.4) was observed for those with GSTM1A, and GSTT1-null genotypes who had consumed a lifetime of >250u2009kg of spirit-equivalents. In conclusion, alcohol consumption may increase breast cancer risk among those who carry susceptible GST genotypes.

Genotoxicity of metal nanoparticles.

Abstract Nanotechnology is currently used in industry, medicine, and military applications, as well as in more than 300 commercial products. Yet, the same properties that make these particles exciting for technology also make them daunting public health concerns because their toxicity is unknown and relatively unexplored. Increased attention is being placed on the study of metal particle genotoxicity; however, a lot of unknowns remain about their effects and the mechanisms. In this article, we highlight some metal and metal oxide nanoparticles of interest and discuss the current in vivo and in vitro studies of genotoxic effects. Many metal nanoparticles were found to cause chromosomal aberrations, DNA strand breaks, oxidative DNA damage, and mutations. Inconsistencies are found in the literature, however, thus drawing conclusions is difficult due to a variety of factors. Therefore, the areas requiring further attention are highlighted and recommendations to improve our understanding of the genotoxic potential are addressed.

A review of the toxicity of chemical dispersants.

Abstract Chemical dispersants are a mixture of various surfactants and solvents. Most dispersants are proprietary, and the complete composition is not often public knowledge. Chemical dispersants used for the cleanup and containment of crude oil toxicity became a major concern after the 2010 Deepwater Horizon oil crisis in the Gulf of Mexico. During the crisis, millions of liters of chemical dispersants (Corexit 9527 and 9500) were used – the largest known application of dispersants in the field. As of February 2011, 38 peer-reviewed articles were available on the toxicity of 35 different chemical dispersants. Nalco, BP, Shell, and Total Special Fluids manufacture a variety of chemical dispersants. Most notably, Nalco manufactures Corexit 9527 and 9500, and 19 miscellaneous dispersants are manufactured by others. Most studies examined the lethality of the dispersants. Several nonlethal end points were considered, including the effect on predator/prey recognition, enzyme activity changes, effects on hatchability, and the threshold for bradycardia. The animals studied included Daphnia (small planktonic crustaceans), anemones, corals, crustaceans, starfish, mollusks, fish, birds, and rats. Studies in birds and mammals are distinctly lacking. The variety of chemical dispersants, the variability in test methods, and the lack of distinct species overlap between studies make it difficult to compare and deduce which dispersant is most toxic and which is least. Here, we offer some attempt at comparing Corexit 9527 and 9500 (because these have had the largest field application), but significantly more research is needed before clear conclusions can be drawn.

Cigarette smoking, glutathione-S-transferase M1 and T1 genetic polymorphisms, and breast cancer risk (United States)

Objective: It has been suggested that functional polymorphisms in genes encoding tobacco carcinogen-metabolizing enzymes may modify the relationship between tobacco smoking and breast cancer risk. We sought to determine if there is a gene–environment interaction between GSTM1 (GSTM1A and GSTM1B), and GSTT1 genotypes and cigarette smoking in the risk of breast cancer. Methods: Cases and controls were recruited in a case–control study conducted in Connecticut from 1994 to 1998. Cases were histologically confirmed, incident breast cancer patients, and controls were randomly selected from women histologically confirmed to be without breast cancer. A total of 338 cases and 345 controls were genotyped for GSTM1 and GSTT1. Results: None of the GSTM1 genotypes, either alone or in combination with cigarette smoking, was associated with breast cancer risk. There was, however, a significantly increased risk of breast cancer among postmenopausal women with a GSTT1 null genotype (OR = 1.9, 95% CI 1.2–2.9). There were also indications of increased risk of breast cancer associated with cigarette smoking for postmenopausal women with GSTT1-null genotype, especially for those who commenced smoking before age 18 (OR = 2.9, 95% CI 1.0–8.8). Conclusion: Women with a GSTT1-null genotype may have an increased breast cancer risk, especially postmenopausal women who started smoking at younger ages.

Particulate hexavalent chromium is cytotoxic and genotoxic to the North Atlantic right whale (Eubalaena glacialis) lung and skin fibroblasts.

Hexavalent chromium compounds are present in the atmosphere and oceans and are established mutagens and carcinogens in human and terrestrial mammals. However, the adverse effects of these toxicants in marine mammals are uncertain. Previously, we reported that North Atlantic right whales, one of the most endangered great whales, have tissue chromium levels that are high, levels that may pose a risk to the whales health. Furthermore, the study suggested that inhalation may be an important exposure route. Exposure to chromium through inhalation is mainly because of particulate compounds. However, the toxicity of particulate chromium compounds in marine mammal cells is unknown. Accordingly, in this study, we tested the cytotoxic and genotoxic effects of particulate hexavalent chromium in primary cultured lung and skin fibroblasts from the endangered North Atlantic right whale. Cytotoxicity was measured by clonogenic survival assay, and genotoxicity was measured as production of chromosome aberrations. Particulate hexavalent chromium induced cytotoxicity and genotoxicity in a concentration‐dependent manner in both right whale lung and skin fibroblasts. Lung fibroblasts were more resistant to chromium cytotoxicity, but presented with more chromosome damage than skin fibroblasts. These data further support the hypothesis that chromium may be a health concern for the endangered North Atlantic right whale. Environ. Mol. Mutagen. 2009.

Global mercury and selenium concentrations in skin from free-ranging sperm whales (Physeter macrocephalus)

Pollution of the ocean by mercury (Hg) is a global concern. Hg persists, bioaccumulates and is toxic putting high trophic consumers at risk. The sperm whale (Physeter macrocephalus), is a sentinel of ocean health due to its wide distribution, longevity and high trophic level. Our aim was to survey Hg concentrations worldwide in the skin of free-ranging sperm whales considering region, gender and age. Samples were collected from 343 whales in 17 regions during the voyage of the research vessel, Odyssey, between 1999 and 2005. Skin was analyzed for total Hg and detected in all but three samples with a global mean of 2.5±0.1 μg g(-1) ranging from 0.1 to 16.0 μg g(-1). The Mediterranean Sea had the highest regional mean with 6.1 μg g(-1) followed by Australia with 3.5 μg g(-1). Considering gender, females and males did not have significantly different global Hg concentrations. The variation among regions for females was significantly different with highest levels in the Mediterranean and lowest in Sri Lanka; however, males were not significantly different among regions. Considering age in males, adults and subadults did not have significantly different Hg concentrations, and were not significantly different among regions. The toxic effects of these Hg concentrations are uncertain. Selenium (Se), an essential element, antagonizes Hg at equimolar amounts. We measured total Se concentrations and found detectable levels in all samples with a global mean of 33.1±1.1 μg g(-1) ranging from 2.5 to 179 μg g(-1). Se concentrations were found to be several fold higher than Hg concentrations with the average Se:Hg molar ratio being 59:1 and no correlation between the two elements. It is possible Hg is being detoxified in the skin by another mechanism. These data provide the first global analysis of Hg and Se concentrations in a free-ranging cetacean.