Association between Polymorphisms of Hemochromatosis (HFE), Blood Lead (Pb) Levels, and DNA Oxidative Damage in Battery Workers.

Occupational exposure to lead (Pb) continues to be a serious public health concern and may pose an elevated risk of genetic oxidative damage. In Brazil, car battery manufacturing and recycling factories represent a great source of Pb contamination, and there are no guidelines on how to properly protect workers from exposure or to dispose the process wastes. Previous studies have shown that Pb body burden is associated with genetic polymorphisms, which consequently may influence the toxicity of the metal. The aim of this study was to assess the impact of Pb exposure on DNA oxidative damage, as well as the modulation of hemochromatosis (HFE) polymorphisms on Pb body burden, and the toxicity of Pb, through the analysis of 8-hydroxy-2'-deoxyguanosine (8-OHdG), in subjects occupationally exposed to the metal. Male Pb-exposed workers (n = 236) from car battery manufacturing and recycling factories in Brazil participated in the study. Blood and plasma lead levels (BLL and PLL, respectively) were determined by ICP-MS and urinary 8-OHdG levels were measured by LC-MS/MS, and genotyping of HFE SNPs (rs1799945, C → G; and 1800562, G → A) was performed by TaqMan assays. Our data showed that carriers of at least one variant allele for HFE rs1799945 (CG + GG) tended to have higher PLL than those with the non-variant genotype (ß = 0.34; p = 0.043); further, PLL was significantly correlated with the levels of urinary 8-OHdG (ß = 0.19; p = 0.0060), while workers that carry the variant genotype for HFE rs1800562 (A-allele) showed a prominent increase in 8-OHdG, as a function of PLL (ß = 0.78; p = 0.046). Taken together, our data suggest that HFE polymorphisms may modulate the Pb body burden and, consequently, the oxidative DNA damage induced by the metal.

Adaptive epigenetic response of glutathione (GSH)-related genes against lead (Pb)-induced toxicity, in individuals chronically exposed to the metal.

It is well known that one of the most outstanding adverse effects related to lead (Pb) exposure is oxidative stress; moreover, recent findings suggest that disturbances of the redox status of cells are associated with epigenetic responses, and metabolism of glutathione (GSH) plays an important role in this process. This study aimed to assess Pb exposure on % methylation of GSH-related genes' promoter regions (%CH3-CpG) and their influence on biomarkers of oxidative stress, in workers exposed to the metal. One hundred nine male workers participated in the study; ICP-MS determined blood lead levels (BLL); biochemical parameters related to redox status, named GSH, glutathione peroxidase (GPX) and glutathione-S-transferase (GST) were quantified by UV/Vis spectrophotometry. Determination of %CH3-CpG of genes GCLC, GPX1, GSR, and GSTP1 were done by pyrosequencing. Inverse associations were seen between BLL and %CH3-CpG-GCLC, and %CH3-CpG-GSTP1. Moreover, metal exposure did not impact GSH, GPX, and GST; however, negative associations were observed between %CH3-CpG-GPX1 and %CH3-CpG-GSTP1, and the activities of GPX and GST, respectively. Taken together, our results give further evidence about adaptive epigenetic response to avoid oxidative damage induced by Pb exposure, allowing a better understanding of the molecular mechanisms related to the metal toxicity.

Polymorphisms of genes related to metabolism of lead (Pb) are associated with the metal body burden and with biomarkers of oxidative stress.

Individual susceptibility to the toxic effects induced by exposure to lead (Pb) may be affected by several variables, such as environmental factors, as well as intrinsic variations among the individuals, which are hypothetically associated to genetic differences in enzymes metabolizing the metal. Aim of the present study was to evaluate the effects of polymorphisms of glutathione (GSH)-genes related to the antioxidant status and Pb metabolism (GCLC, rs17883901 and GCLM, rs41303970) on Pb levels in blood (B-Pb) and plasma (P-Pb), as well as Pb-related effects on activity of glutathione-peroxidase (GPX) and on GSH concentrations. A cross-sectional study with 236 adults (men, >18 years old) was carried out with workers from automotive battery factories, Brazil. B-Pb and P-Pb were determined by ICP-MS; blood GPX and GSH were determined by spectrophotometry and qPCR TaqMan assays were used for genotyping. A questionnaire was applied in order to collect socio-demographic, lifestyle and time of exposure. The mean B-Pb level was 211 ±â€¯118 µg/L and P-Pb was 6.05 ±â€¯7.13 µg/L. GCLM are associated with changes of B-Pb and P-Pb; individuals who carry at least one polymorphic allele for GCLM gene had lower metal levels in the blood and plasma (ß = -1.5; p = 0.0080; ß = -0.12 and p = 0.050). In addition, individuals carrying at least one polymorphic allele for the GCLC gene had higher concentrations of GSH than the non-polymorphic ones, as a function of B-Pb (ß = 0.072; p = 0.029). Significant associations were also observed with GCLC polymorphism on GSH concentrations (as a function of P-Pb), that is, polymorphic individuals tended to have higher concentrations of GSH than non-polymorphic ones (ß = 0.072; p = 0.030), while those individuals who are polymorphic for GCLM had higher activities of GPX, compared to the non-variant genotype (ß = 0.19; p = 0.028). Taken together, our data indicate that polymorphisms related to Pb toxicokinetics modify the metal body burden and Pb-related antioxidant effects.

Lead (Pb) exposure induces disturbances in epigenetic status in workers exposed to this metal.

Previous studies showed that lead (Pb) exposure may modulate gene expression by changes in the epigenetic status. However, little is known about the impact of Pb exposure and alterations on DNA methylation patterns in humans exposed to this metal. The aim of this study was to assess the consequences of exposure to Pb on DNA global methylation, in order to gain a better understanding of the interactions between Pb exposure and epigenetic effects. The study included 100 male workers employed in automotive battery factories from Paraná State, Brazil. Concentrations of Pb in blood (B-Pb) and plasma (P-Pb) were determined by ICP-MS, the percentage (%) of global DNA methylation was determined by quantification of 5-methylcytosine using indirect ELISA, and sociodemographic data collected by questionnaire by trained interviewers. The mean age was 37 ± 10 (18-67 years); 18% of participants were smokers, while 32% reported consumption of alcoholic beverages. The B-Pb and P-Pb levels were 20 ± 11 and 0.56 ± 0.64 µg/dl, respectively; % global DNA methylation was 2.8 ± 1.1% (ranging from 1.1 to 6.5%). B-Pb and P-Pb concentrations were significantly correlated. Furthermore, a marked association was noted between Pb biomarkers and DNA global methylation. Taken together, our data demonstrated that Pb exposure induced alterations on DNA global methylation in workers who were exposed to the metal and consequently may result in disturbances in the regulation of gene expression, leading to potentially several health adverse effect outcomes.

Milk and Dairy Products Intake Is Associated with Low Levels of Lead (Pb) in Workers highly Exposed to the Metal.

Lead (Pb) is a toxic metal, frequently associated with occupational exposure, due to its widespread use in industry and several studies have shown high Pb levels in workers occupationally exposed to the metal. The aim of this study was to evaluate the influence of milk and dairy products (MDP) on Pb levels in blood (B-Pb), plasma (P-Pb), and urine (U-Pb), in workers from automotive battery industries in Brazil. The study included 237 male workers; information concerning diet and lifestyle were gathered through a questionnaire, and B-Pb, P-Pb, and U-Pb were determined by ICP-MS. Mean B-Pb, P-Pb, and U-Pb were 21 ± 12, 0.62 ± 0.73 µg/dL, and 39 ± 47 µg/g creatinine, respectively. Forty three percent of participants declared consuming ≤3 portions/week of MDP (classified as low-MDP intake), while 57% of individuals had >3portions/week of MDP (high-MDP intake). B-Pb and P-Pb were correlated with working time (r s  = 0.21; r s  = 0.20; p < 0.010). Multivariable linear regressions showed a significant influence of MDP intake on B-Pb (ß = -0.10; p = 0.012) and P-Pb (ß = -0.16; p < 0.010), while no significance was seen on U-Pb. Our results suggest that MDP consumption may modulate Pb levels in individuals highly exposed to the metal; these findings may be due to the Pb-Ca interactions, since the adverse effects of Pb are partially based on its interference with Ca metabolism and proper Ca supplementation may help to reduce the adverse health effects induced by Pb exposure.