Association between short-term exposure to ambient air pollutants and biomarkers indicative of inflammation and oxidative stress: a cross-sectional study using KoGES-HEXA data.

BACKGROUND: Air pollution-induced systemic inflammation and oxidative stress are hypothesized to be the major biological mechanisms underlying pathological outcomes. We examined the association between short-term exposure to ambient air pollutants and biomarkers of inflammation and oxidative stress in 2199 general middle-aged Korean population residing in metropolitan areas. METHODS: Serum levels of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor [TNF]-α) and urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured. Daily concentrations of a series of air pollutants (particulate matter [PM]10, PM2.5, SO2, NO2, CO, and O3) were predicted using the Community Multiscale Air Quality modeling system, and participant-level pollutant exposure was determined using geocoded residential addresses. Short-term exposure was defined as the 1- to 7-day moving averages. RESULTS: The multivariable-adjusted linear models controlling for the sociodemographic, lifestyle, temporal, and meteorological factors identified positive associations of PM with IL-1ß, IL-8, IL-10, TNF-α, and 8-OHdG levels; SO2 with IL-10 levels, CO with IL-1ß, IL-10, and TNF-α levels; and O3 with IL-1ß, IL-8, and 8-OHdG levels. O3 levels were inversely associated with IL-10 levels. For each pollutant, the strongest associations were observed for the 7-day average PM and CO with IL-1ß (per 10-µg/m3 increase in PM10: 2.7%, 95% confidence interval [CI] = 0.6-4.8; per 10-µg/m3 increase in PM2.5: 6.4%, 95% CI = 2.4-10.5; per 0.1-ppm increase in CO: 3.3%, 95% CI = 0.3-6.5); the 2-day average SO2 with IL-10 levels (per 1-ppb increase in SO2: 1.1%, 95% CI = 0.1-2.1); and the 7-day average O3 with IL-8 levels (per 1-ppb increase in O3: 1.3%, 95% CI = 0.7-1.9). CONCLUSIONS: Short-term exposure to ambient air pollutants may induce oxidative damage and pro-inflammatory roles, together with counter-regulatory anti-inflammatory response.

Association between dietary cadmium intake and early gastric cancer risk in a Korean population: a case-control study.

PURPOSE: Foods such as grains and vegetables are the dominant sources of exposure to cadmium, which has been classified as a carcinogen by various public health agencies. Cadmium exposure is a growing concern due to its associations with numerous harmful health effects, including gastric cancer risk. The objective of this study was to investigate the association of dietary cadmium intake and the consumption of cadmium-contributing foods with early gastric cancer risk. METHODS: A case-control study including 1245 subjects (cases, 415; controls, 830) was conducted in Korea. The dietary cadmium intake and the consumption of cadmium-contributing foods were assessed using a semi-quantitative food frequency questionnaire. RESULTS: After adjustment for covariates, the gastric cancer risk was increased for participants in the highest tertile of cadmium intake [odds ratios (ORs) 1.33, 95% confidence intervals (95% CIs) 0.94-1.88], but there was no significance. Both female (ORs 2.71, 95% CIs 1.37-5.36) and male (ORs 1.63, 95% CIs 1.07-2.50) participants in the highest tertile of rice consumption had a higher gastric cancer risk than did those in the lowest tertile. Men in the highest tertile of crab consumption had a gastric cancer risk 2.23 times greater than that of men in the lowest tertile (ORs 2.23, 95% CIs 1.21-4.13), but a difference was not seen in women. CONCLUSIONS: Future studies examining the causal effects of dietary cadmium intake and the consumption of cadmium-contributing foods on early gastric cancer risk in large-scale prospective cohorts are recommended.

Genome-wide profiling of normal gastric mucosa identifies Helicobacter pylori- and cancer-associated DNA methylome changes.

The large geographic variations in the incidence of gastric cancer (GC) are likely due to differential environmental exposures, in particular to Helicobacter pylori (H. pylori) infection. We aimed to investigate the impact of H. pylori on the epigenome in normal gastric mucosa and methylation changes associated with cancer risk independent of H. pylori. A discovery set of normal gastric mucosa from GC cases (n = 42) and controls (n = 42), nested in a large case-control study and stratified by H. pylori status, were subjected to genome-wide methylation profiling. Single-nucleotide polymorphism arrays from peripheral blood leukocytes were used to conduct methylation quantitative trait loci (mQTL) analysis. A validation set of gastric mucosa samples (n = 180) was used in the replication phase. We found 1,924 differentially methylated positions (DMPs) and 438 differentially methylated regions (DMRs) associated with H. pylori infection, most of which were hypermethylated. Significant methylation alterations identified in the initial set were successfully replicated. Furthermore, the H. pylori-associated DMP/Rs showed marked stability ('epigenetic memory') after H. pylori clearance. Interestingly, we found 152 DMRs associated with cancer risk independent of the H. pylori status in normal gastric mucosa. The methylation score derived from three biomarkers was a strong predictor of GC. Finally, the mQTL analysis indicated that the H. pylori- and cancer-specific methylation signatures were minimally affected by genetic variation. The comprehensively characterized methylome changes associated with H. pylori infection and GC risk in our study might serve as potential biomarkers for early cancer progression in tumour-free gastric mucosa.

Blood lead concentrations and attention deficit hyperactivity disorder in Korean children: a hospital-based case control study.

BACKGROUND: Because the developing brain of a child is vulnerable to environmental toxins, even very low concentration of neurotoxin can affect children's neurodevelopment. Lead is a neurotoxic heavy metal which has the harmful effect on the striatal-frontal circuit of brain. This area of the brain is known to be closely related to attention deficit hyperactivity disorder (ADHD) pathophysiology. The primary objective of the present study was to investigate whether elevated blood lead concentration is a risk factor for ADHD. The secondary objective was to examine the association between blood lead concentration and symptom severity. METHODS: We conducted a frequency-matched, hospital-based case-control study with 114 medically diagnosed ADHD cases and 114 controls. The participants were matched for age and sex. The diagnoses of ADHD were assessed with semi-structured diagnostic interviews. The participants completed the continuous performance test (CPT), and their parents completed the ADHD-rating scale (ADHD-RS). Blood lead concentrations were measured by using graphite furnace atomic absorption spectrometry featuring Zeeman background correction. RESULTS: Children with ADHD exhibited blood lead concentrations that were significantly higher than those of the controls ( 1.90 ± 086 µg/dℓ vs. 1.59 ± 0.68 µg/dℓ, p = 0.003). The log transformed total blood lead concentration was associated with a higher risk of ADHD (OR: 1.60, 95 % CI: 1.04-2.45, p < 0.05). The analysis also revealed that the children with blood lead concentrations above 2.30 µg/dℓ were at a 2.5-fold (95 % CI: 1.09-5.87, p < 0.05) greater risk of having ADHD. After adjusting for covariates, our multivariate regression models indicated that blood lead concentrations were not significantly associated with ADHD-RS or CPT profiles among the ADHD cases. CONCLUSION: Even low blood lead concentrations are a risk factor for ADHD in children. This study warrants primary prevention policies to reduce the environmental lead burden. Future studies may be required to ascertain the effects of lead on symptom severity in ADHD.

Association between preoperative C-reactive protein level and colorectal cancer survival: a meta-analysis.

PURPOSE: C-reactive protein (CRP) is widely known as a major nonspecific systemic inflammatory marker. A number of previous studies have suggested that elevated preoperative CRP is associated with poor prognosis in colorectal cancer. We aimed to explore the effects of preoperative CRP on colorectal cancer survival through a meta-analysis. METHODS: A total of 21 studies, including a total of 3934 colorectal cancer patients, were eligible. The multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of selected studies were used to assess the summary estimates of the association between preoperative CRP and colorectal cancer survival. RESULTS: The pooled HRs of elevated preoperative CRP for earlier stage patients were 2.04 (95% CI 1.45-2.86) for OS, 4.37 (95% CI 2.63-7.27) for CSS, and 1.88 (95% CI 0.97-3.67) for DFS. The pooled HRs of a higher Glasgow Prognostic Score (GPS)/modified GPS (mGPS) for earlier stage patients were 2.20 (95% CI 1.61-3.02) for OS and 1.80 (95% CI 1.37-2.37) for CSS. The association between elevated preoperative CRP and poor survival was observed in patients with advanced cancer. Elevated CRP and GPS/mGPS were significantly associated with poor survival. CONCLUSION: Preoperative CRP and its related markers, GPS and mGPS, were significantly associated with the survival of colorectal cancer surgery patients. The HRs of GPS and mGPS were highly homogeneous across studies for all survival types. Thus, GPS and mGPS may serve as stable predictors of the survival of colorectal cancer surgery patients.

Gastric and colorectal cancer incidence attributable to dietary factors in Korea.

Background: Dietary factors play a role in the etiology of gastrointestinal cancer. We aimed to estimate the burden of gastric and colorectal cancer that can be attributable to dietary factors in adults aged 20 years and older in Korea in 2018. Methods: Dietary intakes in 2000 were estimated using data from the 2001, 2005, and 2007-2018 Korea National Health and Nutrition Examination Survey (KNHANES). For counterfactual scenarios, the optimal level of intake suggested by the Global Burden of Disease (GBD) study was used if it was available. Otherwise, the average intake values of reference groups among published studies globally were used. Relative risks (RRs) were pooled through dose-response meta-analyses of Korean studies. Results: In Korea in 2018, an estimated 18.6% of gastric cancer cases and 34.9% of colorectal cancer cases were attributed to the combined effect of evaluated dietary factors. High intake of salted vegetables accounted for 16.0% of gastric cancer cases, followed by salted fish at 2.4%. Low intakes of whole grains (16.6%) and milk (13.7%) were leading contributors to colorectal cancer cases, followed by high intakes of processed meat (3.1%) and red meat (5.9%), and a low intake of dietary fiber (0.5%). Conclusions: These results suggest that a considerable proportion of gastric and colorectal cancer incidence might be preventable by healthy dietary habits in Korea. However, further research is needed to confirm the associations between dietary factors and gastric and colorectal cancers in Korea and to formulate and apply effective cancer prevention strategies to Koreans.

Differential influence of dietary soy intake on the risk of breast cancer recurrence related to HER2 status.

The effects of soy products and isoflavone on breast cancer recurrence were compared according to receptor status including epidermal growth factor receptor-2 (HER2) with 339 Korean women. Dietary intake of soy foods was assessed using a validated food frequency questionnaire with 103 food items. Twenty-five patients experienced breast cancer recurrence, 17 patients were HER2 negative, and 8 patients were HER2 positive. Legume intake (mostly from black soybeans) was inversely associated with the risk of breast cancer recurrence in HER2 negative cancer patients (HR: 0.27, 95% CI: 0.13-0.57, P for trend < 0.01), whereas legume intake was positively associated in HER2 positive cancer patients (P for trend = 0.02). In HER2 negative cancer patients, isoflavone was inversely associated with breast cancer recurrence (HR: 0.23, 95% CI: 0.06-0.89; P for trend = 0.01). Total soy intake was not associated with an increased risk of cancer recurrence. In conclusion, overall soy food intake might not affect the risk of cancer recurrence, but high intake of soy isoflavones increased the risk of cancer recurrence in HER2-positive breast cancer patients. However, further research is needed to confirm these results due to the small number of cancer recurrence events.

Association between haemoglobin A1c and all-cause and cause-specific mortality in middle-aged and older Koreans: a prospective cohort study.

BACKGROUND: This study aimed to examine associations between haemoglobin A1c (HbA1c) levels over time and all-cause and cause-specific mortality in middle-aged and older Koreans. METHODS: Using 16 years of follow-up data from the Korean Genome and Epidemiology Study, we analysed 9294 individuals aged 40-69 years with no history of cardiovascular disease (CVD) or cancer. Participants were divided into a known diabetes group and five groups categorized by HbA1c levels (< 5.0%, 5.0-5.4%, 5.5-5.9%, 6.0-6.4%, and ≥ 6.5%). Hazard ratios (HRs) for all-cause and cause-specific mortality associated with HbA1c levels were calculated using a conventional and a time-dependent Cox proportional hazards model. Restricted cubic spline models were fitted to investigate the relationship between continuous HbA1c levels and mortality among people without known diabetes. Subgroup analyses were performed for age, sex, smoking, hypertension, liver diseases, and red blood cell counts. RESULTS: During a median follow-up period of 15.7 years, there were 944 deaths, including 185 deaths from CVD, 359 from cancer, and 125 from all external causes. Compared with participants with HbA1c levels of 5.5-5.9%, multivariate-adjusted HRs and 95% confidence intervals for all-cause death of participants with levels < 5.0%, 5.0-5.4%, 6.0-6.4%, and ≥ 6.5% and participants with known diabetes were 1.84 (1.35-2.51), 1.13 (0.95-1.34), 1.30 (1.04-1.62), 1.37 (0.97-1.93), and 2.03 (1.70-2.44), respectively. The risk of cancer mortality was significantly increased in HbA1c < 5.0% (HR, 2.21; 95% CI 1.42-3.44) and known diabetes (HR, 1.60; 95% CI 1.18-2.15). When we performed diverse subgroup analyses, low HbA1c levels at baseline were strongly associated with mortality in participants with liver diseases. CONCLUSIONS: We found U-shaped associations between HbA1c levels at baseline and over time and all-cause mortality in middle-aged and older Koreans. Additionally, the risk of cancer mortality increased both in low and high HbA1c groups, but CVD mortality increased only in high HbA1c group. In particular, people with liver diseases and low HbA1c levels had a high risk of all-cause mortality. Therefore, more careful management of these groups is suggested to identify any deteriorating health conditions.

Long-Term Effects of Ambient Particulate and Gaseous Pollutants on Serum High-Sensitivity C-Reactive Protein Levels: A Cross-Sectional Study Using KoGES-HEXA Data.

Ambient air pollutants reportedly increase inflammatory responses associated with multiple chronic diseases. We investigated the effects of long-term exposure to ambient air pollution on high-sensitivity C-reactive protein (hs-CRP) using data from 60,581 participants enrolled in the Korean Genome and Epidemiology Study-Health Examinees Study between 2012 and 2017. Community Multiscale Air Quality System with surface data assimilation was used to estimate the participants' exposure to criteria air pollutants based on geocoded residential addresses. Long-term exposure was defined as the 2-year moving average concentrations of PM10, PM2.5, SO2, NO2, and O3. Multivariable linear and logistic regression models were utilized to estimate the percent changes in hs-CRP and odds ratios of systemic low-grade inflammation (hs-CRP > 3 mg/L) per interquartile range increment in air pollutants. We identified positive associations between hs-CRP and PM10 (% changes: 3.75 [95% CI 2.68, 4.82]), PM2.5 (3.68, [2.57, 4.81]), SO2 (1.79, [1.10, 2.48]), and NO2 (3.31, [2.12, 4.52]), while negative association was demonstrated for O3 (-3.81, [-4.96, -2.65]). Elevated risks of low-grade inflammation were associated with PM10 (odds ratio: 1.07 [95% CI 1.01, 1.13]), PM2.5 (1.08 [1.02, 1.14]), and SO2 (1.05 [1.01, 1.08]). The odds ratios reported indicated that the exposures might be risk factors for inflammatory conditions; however, they did not reflect strong associations. Our findings suggest that exposure to air pollutants may play a role in the inflammation process.

Integrated dataset of the Korean Genome and Epidemiology Study cohort with estimated air pollution data.

Public concern about the adverse health effects of air pollution has grown rapidly in Korea, and there has been increasing demand for research on ways to minimize the health effects of air pollution. Integrating large epidemiological data and air pollution exposure levels can provide a data infrastructure for studying ambient air pollution and its health effects. The Korean Genome and Epidemiology Study (KoGES), a large population-based study, has been used in many epidemiological studies of chronic diseases. Therefore, KoGES cohort data were linked to air pollution data as a national resource for air pollution studies. Air pollution data were produced using community multiscale air quality modeling with additional adjustment of monitoring data, satellite-derived aerosol optical depth, normalized difference vegetation index, and meteorological data to increase the accuracy and spatial resolution. The modeled air pollution data were linked to the KoGES cohort based on participants' geocoded residential addresses in grids of 1 km (particulate matter) or 9 km (gaseous air pollutants and meteorological variables). As the integrated data become available to all researchers, this resource is expected to serve as a useful infrastructure for research on the health effects of air pollution.

A Method to Investigate the Helicobacter pylori-Associated DNA Methylome.

The protocol described here for methylome profiling consists of two parts. One is the experimental part for a genome-wide analysis of methylation level, and the other is the bioinformatics analysis of the methylome data. DNA methylation measurement is conducted using the commercially available array-based "Infinium Human Methylation 450K BeadChip" kit (or its updated version, Infinium MethylationEPICBeadChip). This BeadChip allows the high-throughput DNA methylation analysis suitable for genome-wide studies with large sample size. The results give intensities of the beads providing information on the unmethylated and methylated CpG sites. Bioinformatics data analysis involves reading the intensities as methylation values using R packages. Here, we provide a detailed analysis tool for each of the data analysis steps.

Dietary mercury intake and colorectal cancer risk: A case-control study.

BACKGROUND & AIMS: The main source of mercury exposure is food such as fish and shellfish. Mercury is a growing concern due to its associations with a number of harmful health effects, including cancer. The objectives of this study were to examine the association between dietary mercury intake and colorectal cancer (CRC) risk and to determine whether this association differs by anatomical site and menopausal status. METHODS: A case-control study was conducted with 2769 participants (923 cases and 1846 controls) in Korea. Dietary mercury intake and fish and shellfish consumption were assessed using a semiquantitative food frequency questionnaire. RESULTS: A high intake of dietary mercury was associated with an increased risk of CRC (in the group with lower fish and shellfish consumption; odds ratio (OR): 3.13; 95% confidence interval (95% CI): 2.33, 4.71, in the group with higher fish and shellfish intake; OR: 3.84, 95% CI: 2.20, 7.30) after adjusting for all potential confounders by anatomic site in men. Among women, the results differed by fish and shellfish consumption and menopausal status. Regarding the amount of fish and shellfish intake, a positive association was found only in the group with lower intake (CRC; OR: 2.24, 95% CI: 1.36, 3.72, colon cancer; OR: 2.25, 95% CI: 1.22, 4.16, rectal cancer; OR: 2.28, 95% CI: 1.13, 4.57). In the stratified analysis by menopausal status, the elevated risk of CRC was still observed among both pre- and postmenopausal women depending on anatomical site, except for the colon cancer patients with premenopausal status. CONCLUSIONS: A high intake of mercury was associated with an elevated risk of overall CRC. Future large-scale prospective cohort studies are recommended to investigate the causal effects of dietary mercury intake by fish and shellfish consumption on CRC risk depending on anatomical site and menopausal status.

Micronucleus-centromere assay and DNA repair gene polymorphism in lymphocytes of industrial radiographers.

The micronucleus-centromere assay using a pan-centromeric probe was used to assess chromosomal damage in lymphocytes of 47 industrial radiographers occupationally exposed to low dose ionizing radiation and 47 controls. The influence of genotype of DNA repair genes (XRCC1(399), XRCC3(241) and XPD(751)) on micronuclei (MN) frequency was also investigated. Centromere negative micronuclei (MNC-) frequency was significantly higher in radiographers than in controls, whereas similar centromere positive micronuclei (MNC+) frequency was observed in both groups. Poisson regression analyses revealed that the MNC- frequency was significantly associated with radiation occupational exposure and with cumulative-radiation doses in radiographers, after adjusting for confounding variables such as age, smoking, alcohol intake and genotypes. Compared to homozygous wild-type subjects, MNC- frequency in radiographers with variant XRCC3 genotype was significantly higher using univariate analysis. There were no differences in MNC- or MNC+ frequencies by genotype in controls. In conclusion, scoring of MNC- is a useful cytogenetic biomonitoring method for radiographers. Polymorphisms in XRCC3 might contribute to the increased genetic damage in individuals occupationally exposed to chronic ionizing radiation.

Risk assessment of hydroquinone: differential responses of cell growth and lethality correlated to hydroquinone concentration.

Hydroquinone (HQ) is a major metabolite of benzene and has been used as an antioxidant, a stabilizer, a photographic reducer, and an ingredient in skin lighteners. In this study, the effects of low (5 microM) and high (50 microM) concentrations of HQ were investigated on cell growth and lethality in Jurkat cells. Intracellular reactive oxygen species (ROS) levels were increased with both HQ concentrations. Fifty micromolar HQ markedly increased phosphorylation of ERK and activation of caspase-9/-3, followed by PARP cleavage. The addition of ERK inhibitor PD98059 or N-acetylcysteine (NAC) abolished HQ-induced apoptosis. Five micromolar HQ activated ERK protein, but not JNK or p38. However, S-phase recruitment was decreased by preincubation with NAC, but not PD98059. Thus, high levels of ROS contributed to HQ-induced apoptosis via ERK signaling and the caspase pathway, whereas low quantities of ROS resulted in S-phase recruitment in the cell-cycle distribution.

Identification of Dietary Patterns Associated with Incidence of Hyperglycemia in Middle-Aged and Older Korean Adults.

Little is known about the association between dietary patterns and hyperglycemia incidence among Korean adults. Hence, we aimed to prospectively investigate the major dietary patterns associated with hyperglycemia among middle-aged and older Korean adults. In total, 55,457 adults (18,292 men and 37,165 women) aged 40 to 79 years, who were previously enrolled in the Health Examinee Study of the Korean Genome and Epidemiology Study and had no history of type 2 diabetes mellitus (T2DM) or cancer at baseline, were included. Dietary patterns were identified by a factor analysis based on dietary data, which were assessed at baseline using a validated food-frequency questionnaire. Participants were classified as having hyperglycemia if fasting blood glucose levels were ≥126 mg/dL or physician diagnosed T2DM during follow-up. Multivariable Cox proportional hazard models were used to examine the associations between each dietary pattern and future hyperglycemia risk after adjusting for potential confounders. After a mean follow-up of 4.9 years, 2574 new cases of hyperglycemia were identified. Using a factor analysis, four distinct dietary patterns were identified: "prudent;" "fatty fish, meat, and flour-based food;" "coffee and sweets;" and "whole grain (men)" or "white rice (women)." The "prudent" pattern was inversely associated with hyperglycemia risk only in women (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.63-0.89; p for trend = 0.0003). Conversely, women in the highest quintile of the "fatty fish, meat, and flour-based food" pattern showed an increased risk of hyperglycemia (HR, 1.22; 95% CI, 1.03-1.44; p for trend = 0.0210) compared with those in the lowest quintile. The "coffee and sweets" and "white rice" patterns were not associated with hyperglycemia risk in women. The dietary patterns observed in men had no associations with hyperglycemia incidence. Our findings suggest that a diet rich in vegetables, mushrooms, seaweeds, fruits, and soy products and low in fatty fish and high-fat meat may potentially play a protective role in T2DM development with sex differences in middle-aged and older Korean adults.

LINE-1 hypomethylation is associated with radiation-induced genomic instability in industrial radiographers.

Global DNA hypomethylation is proposed as a potential biomarker for cancer risk associated with genomic instability, which is an important factor in radiation-induced cancer. However, the associations among radiation exposure, changes in DNA methylation, and carcinogenesis are unclear. The aims of this study were (1) to examine whether low-level occupational radiation exposure induces genomic DNA hypomethylation; and (2) to determine the relationships between radiation exposure, genomic DNA hypomethylation and radiation-induced genomic instability (RIGI) in industrial radiographers. Genomic DNA methylation levels were measured in blood DNA from 40 radiographers and 28 controls using the LINE-1 pyrosequencing assay and the luminometric methylation assay. Further, the micronucleus-centromere assay was performed to measure aneuploidy of chromosomes 1 and 4 as a marker of delayed RIGI. Genomic DNA methylation levels were significantly lower in radiographers than those in controls. LINE-1 hypomethylation was not significantly correlated with recent 1-year, recent 3-year, or total cumulative radiation doses in radiographers; however, LINE-1 hypomethylation significantly correlated with the cumulative radiation dose without recent 3-year exposure data (D3dose, r = -0.39, P < 0.05). In addition, LINE-1 hypomethylation was a significant contributor to aneuploidy frequency by D3dose (F (2, 34) = 13.85, P < 0.001), in which a total of 45% of the variance in aneuploidy frequency was explained. Our results provide suggestive evidence regarding the delayed effects of low-dose occupational radiation exposure in radiographers and its association with LINE-1 hypomethylation; however, additional studies using more subjects are needed to fully understand the relationship between genomic DNA hypomethylation and RIGI. Environ. Mol. Mutagen. 60: 174-184, 2019. © 2018 Wiley Periodicals, Inc.

Genome-Wide Association of Genetic Variation in the PSCA Gene with Gastric Cancer Susceptibility in a Korean Population.

PURPOSE: Half of the world's gastric cancer cases and the highest gastric cancer mortality rates are observed in Eastern Asia. Although several genome-wide association studies (GWASs) have revealed susceptibility genes associated with gastric cancer, no GWASs have been conducted in the Korean population, which has the highest incidence of gastric cancer. MATERIALS AND METHODS: We performed genome scanning of 450 gastric cancer cases and 1,134 controls via Affymetrix Axiom Exome 319 arrays, followed by replication of 803 gastric cancer cases and 3,693 healthy controls. RESULTS: We showed that the rs2976394 in the prostate stem cell antigen (PSCA) gene is a gastriccancer-susceptibility gene in a Korean population, with genome-wide significance and an odds ratio (OR) of 0.70 (95% confidence interval [CI], 0.64 to 0.77). A strong linkage disequilibrium with rs2294008 was also found, indicating an association with susceptibility. Individuals with the CC genotype of the PSCA gene showed an approximately 2-fold lower risk of gastric cancer compared to those with the TT genotype (OR, 0.47; 95% CI, 0.39 to 0.57). The effect of the PSCA gene on gastric cancer was more prominent in the female population and for diffuse type gastric cancer. CONCLUSION: Our result confirmed that the PSCA gene may be the most important susceptibility gene for gastric cancer risk in a Korean population.

Quercetin prevents necrotic cell death induced by co-exposure to benzo(a)pyrene and UVA radiation.

The phototoxicity of low-energy ultraviolet radiation, such as UVA, can be enhanced by the presence of photosensitizing agents. Hence, co-exposure of cells to benzo[a]pyrene (BaP), a widespread environmental carcinogen and photosensitizing agent, and UVA may synergistically induce DNA damage. In this study, exposure of cells to various concentrations of BaP for 1h followed by UVA irradiation (2J/cm(2)) increased DNA damage and decreased cell viability. Expression of apoptosis-related proteins (caspase-9, caspase-3, PARP, and Bax) and hypodiploid DNA content (sub-G(1)) were not changed. LDH release into the culture medium increased in a dose-dependent manner with BaP under UVA irradiation, suggesting that cell death due to BaP/UVA co-treatment occurred via necrosis. Intracellular reactive oxygen species (ROS) levels were increased significantly in the co-exposed cells, and treatment with the polyphenol quercetin, but not with sodium azide or N-acetylcysteine, decreased ROS levels and increased cell viability in BaP/UVA-treated cells. In conclusion, UVA irradiation combined with BaP synergistically promoted necrosis of A549 cells by increasing intracellular ROS levels, and quercetin prevented BaP-enhanced phototoxicity due to UVA irradiation.

Reoxygenation following hypoxia activates DNA-damage checkpoint signaling pathways that suppress cell-cycle progression in cultured human lymphocytes.

Cellular responses to DNA damage after hypoxia and reoxygenation (H/R) were examined in human lymphocytes. Cultured lymphocytes exposed to H/R showed a lower cytokinesis block proliferation index and a higher frequency of micronuclei in comparison to control cells. Western blots showed that H/R exposure induced p53 expression; however, p21 and Bax expression did not increase, indicating that H/R did not affect p53 transactivational activity. Phosphorylation of p53 (Ser15), Chk1 (Ser345), and Chk2 (Thr68) was also observed, suggesting that H/R activates p53 through checkpoint signals. In addition, H/R exposure caused the phosphorylation and negative regulation of Cdc2 and Cdc25C, proteins that are involved in cell-cycle arrest at the G2/M checkpoint. The S-phase checkpoint, regulated by the ATM-p95/NBS1-SMC1 pathway, was also triggered in H/R-exposed lymphocytes. These results demonstrate that H/R exposure triggers checkpoint signaling and induces cell-cycle arrest in cultured human lymphocytes.

Desferrioxamine (DFX) has genotoxic effects on cultured human lymphocytes and induces the p53-mediated damage response.

Desferrioxamine (DFX), which is an iron chelator, mimics hypoxia by enhancing HIF1-alpha accumulation and upregulating inflammatory mediators. DFX is usually beneficial, with preventive effects related primarily to its ability to scavenge reactive oxygen species. However, toxic effects on skeletal and ocular organs have been reported. The cytokinesis block micronucleus test and alkaline single-cell gel (Comet) assay were used to evaluate the genotoxic effects of DFX on human blood lymphocytes. Cultured human lymphocytes treated with 130microM DFX for various periods of time showed significant differences in the incidence of micronucleated binucleate cells, as well as in the length and moment of the comet tail. Western blot analysis using antibodies to proteins involved in the p53-mediated response to DNA damage revealed that p53 was accumulated and DNA damage checkpoint kinases were activated in lymphocytes treated with DFX. On the other hand, the p53 downstream target proteins p21 and bax were not affected, which indicates that DFX does not promote the transactivational activity of p53. Apoptosis assays demonstrated DFX-induced apoptosis of lymphocytes via the caspase cascade. The observed increase in the sub-G1 fraction and enhanced caspase-3 activity indicate that DFX can promote apoptosis in human lymphocytes, and these results were confirmed by protein immunoblot analysis. As apoptotic cell death is preceded by the collapse of the mitochondrial membrane potential, we also measured the mitochondrial membrane potential (Deltapsi(m)) using DiOC6, which is a fluorescent membrane potential probe. The fluorescence intensity of DiOC6 in lymphocytes was significantly reduced in a time-dependent manner after DFX treatment. Taken together, these results indicate that DFX activates p53-mediated checkpoint signals and induces apoptosis via mitochondrial damage in human peripheral blood lymphocytes.