Interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and between genes and physical activities on physical performance in community-dwelling elders.

This study assessed the interactions among IGF-1, AKT2, FOXO1, and FOXO3 variations and the interactions of gene and physical activity on handgrip strength, arm muscle mass-adjusted handgrip (armGrip), gait speed (GS), timed up and go (TUG), and leg press strength (LPS). Nine single nucleotide polymorphisms (SNPs) containing three IGF-1 SNPs (rs6214, rs5742692, and rs35767), two AKT2 SNPs (rs892119 and rs35817154), two FOXO1 SNPs (rs17446593 and rs10507486), and two FOXO3 SNPs (rs9480865 and rs2153960) were genotyped in 472 unrelated elders with a mean age of 73.8 years. We observed significant interactions of IGF-1 SNP rs6214 and rs35767 with regular physical activity on TUG and GS; and AKT2 SNP rs892119 and FOXO3 SNP rs9480865 with regular physical activity on armGrip. Genotype GG of IGF-1 rs6214 and rs35767 in individuals without regular physical activity had poor performance in TUG and GS, as well as GG of AKT2 rs892119 decreased armGrip in individuals without regular physical activity. After FDR adjustment, no significant gene-gene interactions were found. A sedentary lifestyle may increase the risk of impairing physical performance and regular physical activity is a remedy for sarcopenia, even a little regular physical activity can overcome carrying some risk alleles in this pathway.

Important gene-gene interaction of TNF-α and VDR on osteoporosis in community-dwelling elders.

Gene effects on osteoporosis have been studied separately and may have been masked by gene-gene and gene-environment interactions. We evaluated gene-gene and gene-physical activity interactions of the variants of tumor necrosis factor-α (TNF-α) and vitamin D receptor (VDR) genes on osteoporosis. A total of 472 elders were included. Seven variants (TNF-α: rs1799964, rs1800629, rs3093662; VDR: rs7975232, rs1544410, rs2239185, rs3782905) were genotyped. Bone mineral densities of the lumbar spine, femoral neck, and total hip were measured by dual-energy X-ray absorptiometry. Predictive models' ability to discriminate osteoporosis status was evaluated by areas under the receiver operating characteristics (AUROC) curve. After multivariable adjustment, significant interactions of TNF-α rs1800629 and VDR rs3782905 were observed on overall and lumbar spine osteoporosis. In elderly women, we found that those carrying the CG/CC genotype of VDR rs3782905 were significantly associated with increased odds of overall osteoporosis compared with those carrying the GG genotype of VDR rs3782905 among those carrying TNF-α rs1800629 GG genotype. The adjusted odds ratios (ORs) for VDR rs3782905 CG/CC genotype in elderly women carrying TNF-α rs1800629 AG/AA and GG genotypes were 0.1 (0.01, 0.98) and 3.54 (1.51, 8.30), respectively. We observed significant differences in AUROCs between the model with traditional covariates plus variants and their interaction term and the model with traditional covariates only (AUROCs: 0.77 and 0.81; p = 0.028). Although the sample size of this study may have been relatively small, our results suggest that the interaction of the CG/CC genotype of VDR rs3782905 with TNF-α rs1800629 GG genotype was associated with increased odds of overall and lumbar spine osteoporosis in elderly women.

Gene-physical activity interactions in lower extremity performance: inflammatory genes CRP, TNF-α, and LTA in community-dwelling elders.

We assessed gene-gene and gene-physical activity interactions of polymorphisms in C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and lymphotoxin α (LTA) genes on lower extremity performance in community-dwelling elders in Taiwan. Five SNPs (rs1205, rs1130864, rs1800947, rs2794520, and rs3093059) of CRP gene, three SNPs (rs909253, rs1041981, and rs2239704) of LTA gene, and three SNPs (rs3093662, rs1800629, and rs1799964) of TNF-α gene of 472 unrelated elders were genotyped. Lower extremity performance included timed up-and-go test (TUG), walking speed, weight-adjusted leg press (waLP), and timed chair stand (TCS). We detected significant interactions between physical activity with CRP rs2794520, rs1205, and rs3093059; LTA rs909253 and rs1041981; and TNF-α rs1799964 for TCS in women after covariate adjustment (all P < 0.05). In men, significant interactions between physical activity with CRP rs2794520, rs1205, and rs3093059; and LTA rs909253 and rs1041981 for TUG; with CRP rs2794520, rs1205, rs1130864, and rs3093059; and LTA rs909253 and rs1041981 for walking speed; and with TNF-α rs3093662 for waLP after covariate adjustment (all P < 0.05). These variants also significantly interacted with physical activity on TCS in women and on walking speed in men. These results show inflammatory genes are involved in lower extremity performance, likely via gene-physical activity interactions.

Associations of TNF-α and IL-6 polymorphisms with osteoporosis through joint effects and interactions with LEPR gene in Taiwan: Taichung Community Health Study for Elders (TCHS-E).

Osteoporosis (OST) is a complex multifactorial disease considered to result from interactions of multiple gene and environmental factors. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 are pleiotropic cytokines essential for bone remodeling; and hormone leptin has immunomodulatory effects that stimulate the synthesis of IL-6 and TNF-α. Leptin is involved in the modulation of bone growth and turnover; and its actions are bound by leptin receptor (LEPR). Prior studies evaluated the effects of TNF-α, IL-6, and LEPR gene polymorphisms separately on bone mineral densities (BMD) or OST. In this study, we assessed the roles of TNF-α and IL-6 gene polymorphisms in OST through joint effects and interactions with LEPR gene. We also evaluated possible joint effects and interactions between these polymorphisms and physical activity. Ten tag-SNPs (rs1799964, rs1800629, rs3093662 in TNF-α; rs1880243, rs1800796, rs1554606 in IL-6; and rs1751492, rs8179183, rs1805096, rs1892534 in LEPR) were used to genotype 103 OST cases and 369 controls. BMD of lumbar spine (LS), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry. Our data showed that TNF-α and IL-6 polymorphisms were associated with overall and site-specific OST in both sexes, and that these associations were dependent on rs1805096 and rs1892534 genotypes of LEPR. In men, LEPR A-G-G-G haplotype was associated with FN OST (OR 4.65, 95 % CI 1.61-13.40, p = 0.004). Genotype AA/AG of LEPR rs1751492 was associated with overall and FN OST in women without physical activity, but not in women with physical activity (p < 0.05 for interaction between physical activity and LEPR rs1751492). In men, we detected significant interactions of IL-6 rs1800796 with LEPR rs1805096 and rs1892534 for FN and TH OST (all p < 0.05). Our data indicate that LEPR gene may play joint and interactive roles with TNF-α and IL-6 genes and physical inactivity in development of OST. Haplotype analyses revealed that the correlations tended to be prominent in men with FN OST.

Joint effect of gene-physical activity and the interactions among CRP, TNF-α, and LTA polymorphisms on serum CRP, TNF-α levels, and handgrip strength in community-dwelling elders in Taiwan - TCHS-E.

This study assesses interactions of tumor necrosis factor α (TNF-α) gene polymorphisms with C-reactive protein (CRP) or lymphotoxin α (LTA) gene on serum CRP and TNF-α levels and handgrip strength. Eleven single nucleotide polymorphisms (SNPs), including rs2794520, rs1205, rs1130864, rs1800947, and rs3093059 in CRP; rs1799964, rs1800629, and rs3093662 in TNF-α; and rs2239704, rs909253, and rs1041981 in LTA, were genotyped in 472 unrelated elders (mean age 73.8 years). Among elders with TNF-α rs1799964 AA genotype, adjusted mean difference for handgrip strength decreased by -2.60 (-4.82, -0.38) and -2.51 kg (-4.75, -0.28) for LTA rs909253 and rs1041981 in women and by -2.39 kg (-3.98, -0.81) for CRP rs3093059 in men. Among elders with TNF-α rs1799964 AA genotype, adjusted mean ratios for hs-CRP levels increased by 2.32 (1.38, 3.90) and 2.27 (1.35, 3.84) for both CRP rs909253 and rs1041981 in women. The A-A-C LTA haplotype was associated with TNF-α levels that were 1.55 times higher than those of the C-G-A haplotype (P = 0.005). The joint effects of SNPs (the rs1800947 or rs3093059 of CRP, rs1799964 or rs1800629 of TNF-α, and rs909253 or rs1041981 of LTA) and physical inactivity appeared to have greater magnitude of decreased handgrip strength than main effects of these SNPs and physical inactivity. Our data showed that significant interactions of TNF-αrs1799964 and LTA rs909253 were observed. Moreover, joint effects of these CRP, TNF-α, and LTA risk alleles with physical inactivity in elders were observed, suggesting that physical activity may modulate effects of genotypes on handgrip strength.

Tumor site- and stage-specific associations between allelic variants of glutathione S-transferase and DNA-repair genes and overall survival in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy.

INTRODUCTION: Our retrospective cohort study investigated the effect of tumor site and stage on the associations between the allelic variants of glutathione S-transferase (GST) and DNA-repair genes and overall survival (OS) in CRC patients treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy. MATERIAL AND METHODS: We genotyped GSTM1, GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln in 491 CRC patients between 1995 and 2001. A Cox proportional-hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between the allelic variants and OS. Survival analyses were performed for each allelic variant by using the log-rank test and Kaplan-Meier analysis. RESULTS: The CRC patients with the XPD Gln allelic variants had poorer survival than patients with the Lys/Lys genotype (HR  =1.38, 95% CI  =1.02-1.87), and rectal cancer patients had the poorest survival among them (HR  =1.87, 95% CI  =1.18-2.95). A significantly shorter OS was observed among stage II/III colon cancer patients with the XRCC1 Gln allelic variants (HR  =1.69, 95% CI  =1.06-2.71), compared to those with XRCC1 Arg/Arg genotype. In the combined analysis of the XRCC1 and XPD genes patients with stage II/III tumors, the poorest OS occurred in colon cancer patients with the XRCC1 Gln and XPD Gln allelic variants (HR  =2.60, 95% CI  =1.19-5.71) and rectal cancer patients with the XRCC1 Arg/Arg and XPD Gln allelic variants (HR  =2.77, 95% CI  =1.25-6.17). CONCLUSION: The XPD and XRCC1 allelic variants may be prognostic markers for CRC patients receiving 5-FU based chemotherapy. The contributions of the XPD and XRCC1 allelic variants to OS are tumor site- and/or stage-dependent.

Associations between genetic polymorphisms of epidermal growth factor receptor (EGFR) and survival of colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy.

PURPOSE: This retrospective cohort study investigated the association between epidermal growth factor receptor (EGFR) polymorphisms and clinical outcomes in colorectal cancer (CRC) patients treated with 5-fluorouracil (5-FU)-based chemotherapy. METHODS: We genotyped 3 EGFR polymorphisms including R497K, G-216T, and the (CA)n repeat, among 499 histologically confirmed CRC patients who had received 5-FU-based chemotherapy after surgery between 1995 and 2001. Survival analyses of EGFR polymorphisms were performed by the log rank test and Kaplan-Meier curves. We used the Cox proportional hazard model to evaluate the association between EGFR genotypes and clinical outcomes. Stratification analysis by gender, tumor stage, and subsite were also carried out. RESULTS: CRC patients with the EGFR (CA)n L/L genotype compared to those with the S/S+S/L genotype had a significantly better overall survival (L, ≥ 20 repeats; S, <20 repeats) (hazard ratio (HR) 0.74; 95 % confidence interval (CI) 0.57-0.95), particularly for patients who were male (HR 0.63; 95 % CI 0.44-0.90), who had stage IV disease (HR 0.70; 95 % CI 0.49-0.99), and who had rectal cancer (HR 0.62; 95 % CI 0.42-0.92). Better survival was prominent among patients with the combined genotypes of EGFR (CA)n L/L, G-216T G/G, and R497K K/K (HR 0.51; 95 % CI 0.30-0.87), compared to those with the most common genotypes of the EGFR (CA)n S allele, G-216T G/G, and R497K R allele. CONCLUSIONS: EGFR polymorphisms can serve as prognostic predictors for CRC patients receiving 5-FU-based chemotherapy.

Protein carbonyl levels, glutathione S-transferase polymorphisms and risk of colorectal cancer.

Oxidative stress has been associated with the carcinogenesis of colorectal cancer. Glutathione S-transferases (GSTs) modulate the elimination of free radical. We conducted a case-control study to examine the interaction between oxidative stress and GSTs polymorphisms on colorectal cancer risk. This study recruited 727 pathologically confirmed colorectal adenocarcinoma cases and 736 sex- and age-matched controls. Plasma protein carbonyls, as a parameter of oxidative stress, were measured using enzyme-linked immunosorbent assay. Genotypes of GSTM1, GSTT1 and GSTP1 genes were determined using polymerase chain reaction methods. The protein carbonyl levels were significantly higher in cases than in controls and exerted a dose-response relationship (P for trend < 0.001). Compared with the first carbonyl quartile subjects, those in the second, third and fourth quartiles had odds ratios (ORs) of 1.54 [95% confidence interval (CI) = 1.13-2.10], 1.52 (95% CI = 1.11-2.07) and 1.98 (95% CI = 1.46-2.67), respectively. This effect was significantly modified by GSTM1 genotype (P for interaction = 0.037). The three-way interaction analysis revealed that interactions between GSTM1 genotype and cigarette smoking and between GSTT1 genotype and alcohol drinking further modified the oxidative stress contribution for colorectal cancer (p for interaction were 0.067 and 0.054, respectively). The impact of oxidative stress was more prominent among ever-smokers with GSTM1-null genotype (OR = 3.45, 95% CI = 1.70-6.97) and ever-drinkers with GSTT1-present genotype (OR = 3.87, 95% CI = 1.82-8.25). Our results indicate that interaction between oxidative stress and GSTs polymorphisms may play an important role in the pathogenesis of colorectal cancer.

Recombinant ORF66 and ORFK12 antigens for the detection of human herpesvirus 8 antibodies in HIV-positive and -negative patients.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), is not routinely isolated in cell cultures, and thus detection of HHV-8-specific antibodies is usually performed. In this study, we performed recombinant antigens ORF66- and ORFK12-based Western blot strip assays and ELISA, and surveyed the seroprevalence of HHV-8 antibodies in HIV-positive and -negative patients. In serum samples from patients with positive plasma HHV-8 DNA, the sensitivity of the Western blot strip assay was 100% for the anti-ORF66 antibodies and 83.3% for the anti-ORFK12 antibodies. In addition, ORF66-based ELISA showed higher levels of specificity (87.3%) and sensitivity (84.8%) than ORFK12-based ELISA. Moreover, the area under the receiver-operating characteristics curves (AUROC) was 0.76 for ORF66-based ELISA and 0.66 for ORFK12-based ELISA. The seroprevalence of HHV-8 antibodies to ORF66 and/or ORFK12 in the HIV-infected patients (55%, 97/176) was significantly higher than in the DM patients (45%, 135/301) (P = 0.03) and the HIV-/DM-negative group (11%, 11/100) (P < 0.01). In the HIV-infected patients, the seropositivity of the HHV-8-specific antibody was 30% to both antigens, 19% to ORFK12 and 5.7% to ORF66. Importantly, HHV-8 seropositivity in the HIV-infected patients was significantly associated with the transmission method of intravenous injection and high levels of HIV RNA loading (P < 0.01), but not with gender, CD4 cell numbers or AIDS symptoms. This study assessed the sensitivity and specificity of ORF66 and ORFK12 for the detection of HHV-8 antibodies, providing novel antigens for the diagnosis of HHV-8 infection and epidemiology of HHV-8 seroprevalence.

Prenatal smoking exposure and neonatal DNA damage in relation to birth outcomes.

This study investigated whether mothers with prenatal environmental tobacco smoke (ETS) exposure increased the newborn genetic damage and adverse birth outcomes. Study participants were women receiving prenatal care at three hospitals in Central Taiwan and their newborns. Participants were divided into two groups (nonsmokers and ETS-exposed non-smokers) based on maternal ETS-exposed status. Comet assay were performed for cord blood samples. Infants born to mothers with prenatal ETS exposure had the highest mean cord blood DNA damage score (69.7 +/- 42.3) and poorer birth outcomes. No negative fetal growth effects appeared among newborns with low DNA damage levels. Among newborns with high DNA damage levels (comet scores >50), those born to prenatal ETS exposure had an average reduction of 252.7 g in birth weight, 1.10 cm shorter in length and a 0.92-cm decrease in head circumference, compared to newborns with no smoking exposure. This study shows that the DNA damage scores can be used as an effect-modifier on the relationships between ETS exposure and adverse birth outcome. The association appears more apparent for the ETS exposure in relation with more severe DNA damage.

Comparative prevalence of plasma human herpesvirus 8 DNA in sexual contact and intravenous injection routes of HIV transmission.

Detection of plasma human herpesvirus (HHV)-8 DNA correlates with antibodies to lytic HHV-8 antigens, being predictive of Kaposi's sarcoma in HIV-infected patients. We show that the prevalence of plasma HHV-8 DNA was 10.6% for HIV infection through sexual contact and 7.1% for HIV infection through intravenous injection. In addition, the prevalence of plasma HHV-8 DNA was significantly associated with male gender (9.4%) and HIV viral load below 1000 copies mL(-1) (12.1%), but not age or CD4 cell count in HIV-infected patients. The study suggested that detection of plasma HHV-8 DNA could be important for monitoring replicating HHV-8 in HIV-infected patients, and may have use as a marker for the diagnosis of HHV-8 infection in blood-borne transmission.

Humic acid induced genotoxicity in human peripheral blood lymphocytes using comet and sister chromatid exchange assay.

Humic acid (HA) in well water used by the inhabitants for drinking is one of the possible etiological factors for blackfoot disease (BFD). Moreover, within BFD endemic areas cancers occur at significantly higher rates than in areas free of BFD. In this study, the genotoxic potential of HA is assessed using human peripheral blood lymphocytes. The cells were exposed to HA (0-200 microg/mL for 2 h), and the induction of DNA primary damage in cellular DNA was evaluated by single-cell gel electrophoresis (comet assay). HA-induced DNA damage was decreased by superoxide (O(2)(-)), hydrogen peroxide (H(2)O(2)), and reactive oxygen species (ROS) scavengers (superoxide dismutase, catalase, and Trolox), and nitric oxide (NO) synthase inhibitors (N(G)-nitro-l-arginine methyl ester and N(G)-methyl-l-arginine). Moreover, formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease III (Endo III), known to catalyze the excision of oxidized bases, increase the amount of DNA migration in HA-treated cells. Pretreatment of the cells with both the Ca(2+)-chelator BAPTA and EGTA completely inhibited HA-induced DNA damage, indicating that HA-induced changes in Ca(2+)-homeostasis are the predominant pathways for the HA induction of genotoxicity. Furthermore, sister chromatid exchange was found in the HA-treated lymphocytes. Our findings suggest that HA can induce oxidative DNA damage and genotoxicity in human lymphocytes.

Associations among genetic susceptibility, DNA damage, and pregnancy outcomes of expectant mothers exposed to environmental tobacco smoke.

This study determined the effects of environmental tobacco smoke (ETS) on fetal growth by measuring neonatal birth outcomes and the extent of maternal DNA damage, and investigating the relationships among gene polymorphisms, genotoxicity, and pregnancy outcomes of expectant mothers who had exposed to tobacco smoke. This prospective study enrolled 685 pregnant women who completed an initial questionnaire at three central Taiwan hospitals between 2003 and 2004. Genotype analyses of CYP1A1, GSTT1, GSTM1, and NAT2 were performed from 421 women. A total of 398 women completed the follow-up analysis and successfully delivered a live single baby (n=384). Comet assay was performed for 18 smokers, 143 ETS-exposed subjects and 130 non-smokers to measure DNA damage. Analytical findings indicated that the levels of DNA damage among smokers and ETS-exposed subjects were significantly higher than that of non-smokers. DNA damage score in the ETS-exposed group was 84.3+/-44.3 and 63.5+/35.0 [corrected] for the nonsmoking group (p<0.001). Risk of DNA damage (DNA strand breakage, sister chromatid exchange, cell transformation and escalation of cytotoxicity) for subjects exposed to ETS was 7.49 times (adjusted odds ratio; 95% CI, 1.27-44.20) [corrected] greater than that of non-exposed to tobacco smoke at home. Average birth weight of neonates born to subjects with extremely serious DNA damage (within the 90th percentile, DNA damage score >or =129.5) was 141 g lighter than that of those with DNA damage score <129.5 (p=0.068) [corrected] The degree of DNA lesion was not related to metabolic polymorphic genes. The results of this study suggest that comet assay are reliable biomarkers for monitoring pregnant women exposed to tobacco smoke and indicate fetal growth effects from environmental exposure to tobacco smoke.

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and genetic polymorphisms in breast cancer patients.

Reactive oxygen species (ROS) causes damage to DNA, but the role of ROS in breast carcinoma is still not clear. The objective of this study was to measure the urinary 8-OHdG levels of breast cancer patients at each stage of carcinogenesis and assess its association with the development of breast cancer. Sixty patients with malignant breast tumors were matched with 60 control subjects of the same ages in this case control study. Urinary 8-OHdG levels were significantly higher among breast cancer patients than among the control subjects, after making adjustments for confounders such as smoking, coffee consumption and use of oral contraceptives. The breast cancer patients were divided into three groups based on the stages of their cancer; urinary 8-OHdG levels decreased with each stage of breast carcinoma. Using multiple regression and logistic models adjusted for other covariates, urinary 8-OHdG levels significantly correlated with the development of breast cancer. However, it was found that breast cancer was not significantly influenced by CYP1A1, CYP1M1 or NAT2 polymorphisms. In conclusion, it was found that oxygen radical generation occurred within carcinoma cells, but the role of polymorphism of specific genes in the development of breast cancer should be evaluated.

Association between blood lead level and blood pressure in aborigines and others in central Taiwan.

To investigate the relationship between the blood lead level (BLL) and blood pressure among aborigines and non-aborigines in central Taiwan, a community-based survey that included demographic data, medical history, and blood chemistry analyses was conducted among 2,565 adults during an annual health examination. BLLs were analyzed using a graphite furnace atomic absorption spectrometer (AAS). There was a dose response among the non-aborigines (high BLL odds ratio = 2.97, compared with low BLL) but not among aborigines. Based on multiple linear regression models, BLLs were positively correlated with both systolic (an increase of 0.85 mm Hg/microg/dL) and diastolic (an increase of 0.48 mm Hg/microg/dL) blood pressures after adjusting for age, gender, ethnic group, alcohol consumption, and body mass index. BLLs were higher among aborigines than non-aborigines and were significantly correlated with blood pressure, particularly systolic pressure. The association should be considered causal.

Anti-inflammatory potential of Antrodia Camphorata through inhibition of iNOS, COX-2 and cytokines via the NF-kappaB pathway.

Antrodia camphorata (A. camphorata), well known in Taiwan as a traditional Chinese medicine, has been shown to exhibit antioxidant and anticancer effects. In the present study, therefore, we have examined the effects of the fermented culture broth of A. camphorata (25-100 microg/ml) in terms of lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production, and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in RAW 264.7 macrophages. Our results indicate concentration-dependent A. camphorata inhibition of LPS-induced NO and PGE2 production, without appreciable cytotoxicity on the RAW 264.7 cells. A. camphorata also attenuates the production of LPS-induced tumor necrosis factor (TNF-alpha) and interleukin (IL)-1beta. Furthermore, A. camphorata blocks the IkappaB-alpha degradation induced by LPS. These results indicate that A. camphorata inhibits LPS induction of cytokine, iNOS and COX-2 expression by blocking NF-kappaB activation. Therefore, we report the first confirmation of the anti-inflammatory potential of this traditionally employed herbal medicine in vitro.

Lack of association of delta-aminolevulinic acid dehydratase genotype with cytogenetic damage in lead workers.

OBJECTIVE: The objective of this study was to evaluate the correlations of genetic polymorphism of genotypes delta-aminolevulinic acid dehydratase (ALAD), blood lead levels (BLLs), zinc protoporphyrin (ZPP), sister chromatid exchanges (SCEs), and high SCE frequency cells (HFCs) in lead workers. METHODS: Three groups of lead workers were included in the study: high lead exposure group (26 workers), low lead exposure group (31 workers) and control group (30 controls who lived in an area uncontaminated by lead). Blood samples were taken from all subjects and analyzed for lead levels, ALAD genotype and SCE levels. RESULTS: Occupationally exposed workers had significantly higher BLLs, ZPP and hemoglobin levels than the controls. There were no differences among the three groups regarding percentages of ALAD 1-1 and ALAD 1-2 genotypes, but the ALAD 2-2 genotype was not detected in any of the three groups. There were no significant differences among the three groups for BLLs, ZPP and hemoglobin levels based on ALAD 1-1 and ALAD 1-2. Average SCE values in the high lead exposure group were significantly greater than those in the control group (6.2 vs 5.2 SCEs/cell, P < 0.05). HFC analysis revealed a significantly higher HFC percentage (53.9%) in the high lead exposure group than in the low lead exposure group (16.1%) and the control group (10%). There appeared to be an interaction effect on HFC percentages between smoking and lead exposure. When multiple regression analysis was used, the factors that affected SCE levels were lead exposure and smoking, but ALAD genotypes did not have any significant effect. CONCLUSIONS: A significant association existed between both SCE and HFC levels and lead exposure. However, different ALAD genotypes were not found to be associated with levels of blood lead and ZPP in the three groups.

Association of DNA-protein crosslinks and breast cancer.

This study examined the possible effect of cytochrome P450 (CYP1A1), glutathione S-transferase (GSTM1 and T1) and N-acetyltransferases 2 (NAT2) polymorphisms on DNA-protein crosslinks (DPC) formation in the white blood cells of breast cancer patients, and assessed the levels of DPC detected. Sixty cases of breast cancer were examined, all involving women diagnosed with primary, histopathologically confirmed breast cancer at the Chinese Medical College Hospital in central Taiwan. Additionally, 60 healthy women without breast cancer were selected as a control group, matched by age, cigarette smoking habits, and history of breast cancer among first-degree relatives. Known risk factors for breast cancer, including menarche before 13 years of age (OR=3.2; CI, 1.1-9.5), no history of breast-feeding (OR=4.7; CI, 1.5-14.4) and use of oral contraceptives (OR=9.1; CI, 2.8-29.8), were found to be significantly associated with breast cancer. For the CYP1A1 MspI polymorphism, 16.7 and 18.3% of cases and controls, respectively contained both alleles with the MspI restriction fragment length polymorphism (RFLP). Regarding the NAT2 allele, 25.0 and 21.7% of cases and controls carried slow genotypes. For GSTM1 and GSTT1, 56.7 and 45.0% of cases, as well as 58.3 and 43.3% of controls, contained the null genotype. Meanwhile, chi(2)-tests found no significant differences between the groups. After controlling for confounders such as cigarette smoking and family history of breast cancer, the DPC value of the case group significantly exceeded that of the control group (1.62% versus 0.98%, P<0.001). In conclusion, our findings were inconsistent with those of previous studies that showed polymorphism genes (CYP1A1, NAT2, GSTM1 and GSTT1) were associated with cancer risk. However, this study indicated that genotypic variants of these polymorphisms did not elevate the risk for breast cancer, individually or interactively. Additionally, this investigation represents the first description of the use of DPC as a biomarker to assess the level of DNA damage of breast cancer patients. Our data suggest that the DPC method is a useful tool for detecting DNA damage, and DPC formation may be associated with the induction of breast cancer.

Correlations of blood lead with DNA-protein cross-links and sister chromatid exchanges in lead workers.

Levels of sister chromatid exchanges (SCEs), high-SCE frequency cells (HFCs), DNA-protein cross-links (DPCs), blood lead (BLL), and zinc protoporphyrin (ZPP) were measured in peripheral blood from three groups. The lead workers were divided into two groups: a high BLL group (> or =15 microg/dl) and a low BLL group (<15 microg/dl). The control subjects were selected from an area that had not been contaminated with lead and had normal BLL and ZPP levels. In addition, exposure to airborne lead was measured for 11 lead workers, and the time-weighted average was shown to range from 0.19 to 10.32 mg/m(3). The BLL levels of 9 of 11 workers were >15 microg/dl, of which, 3 exceeded current exposure limits (> or =40 microg/dl). The BLL levels of all 11 controls were < 15 microg/dl. The average SCE and DPC values for the workers were 6.1 SCEs/cell and 1.9%, which were significantly higher (P < 0.01, Wilcoxon's test) than the value of 5.2 SCEs/cell and 1.1% for the control subjects. Lead workers had significantly higher BLL and ZPP levels than did the controls. Statistically significant increases in DPCs, SCEs, and HFCs were observed for the high-BLL group compared with the control group. The results of this study suggest that DPCs, SCEs, and HFCs are reliable biomarkers for monitoring workers exposed to lead and clearly indicate health effects from occupational exposure to lead.