Specimens of human placental DNA were tested for chemical addition products (adducts) by recently developed 32P-postlabeling and immunologic assays, and results were compared with data concerning maternal exposures and birth weight. A total of 7 different adducts were detected in the 53 specimens of human placental tissue examined by the 32P-postlabeling assay. Three of these adducts were found almost exclusively in smokers. Among smokers there were positive dose-response relationships between levels of the smoking-related adducts and biochemical estimates of doses of maternal exposure to cigarette smoke during pregnancy. Levels of 1 adduct found only in smokers appeared to relate directly to amounts of caffeine consumption by the mother. In addition to these relationships with maternal exposures, levels of smoking-related adducts were inversely associated with the birth weight of offspring. Results from this study suggest that even at their current formative stage of development, assays for DNA adducts may help identify determinants of DNA damage to human tissues and improve our ability to demonstrate dose-response relationships for the effects of environmental exposures to potentially carcinogenic agents.
Several bioindicators were used to evaluate the biological and genotoxic effects of marine pollutants near large coastal cities in the northwestern part of the Mediterranean Sea. Three target species of teleosts were selected: red mullet A/lullus barbatus and 2 types of comber (Serranus hepatus and S. cabrilla). Induction of ethoxyresorufin-0-deethylase (EROD) activity specific for polycyclic aromatlc hydrocarbons (PAH) and polychlorinated biphenyls (PCB) was measured in the livers of the fish, and inhibition of acetylcholinesterase (AChE) by organophosphorus insecticides and carbamates was measured in their muscle tissues. Maximal EROD activities (16.8 ? 2.7 to 19.4 & 4.2 pm01 min" mg protein') recorded in red mullet near Barcelona (Spain), Milazzo (Sicily) and Ostia (Italy) indicated exposure to high pollutant concentrations. Inhibitions of AChE activity were low in areas remote from agricultural and industrial activity. The highest inhibitions wel-e measured at sites of heavy industrial and domestic waste, such as C;rnoa and Naples (Italy), Rio Ter ( S p a n ) , Barcelona, and Cortiou (France), Inhibition of AChE activity was higher at a given stdtion for younger ind~viduals 120 to 140 mm in length than for those 160 to 180 mm long. Antioxidant enzyme actlvit~es (catalase, superoxide dlsmutase, glutathione peroxidase and DT-diaphorase) were measured in red mullet livers at 5 stations along the French and Spanish coasts. Catalase activity was highest at Cortiou, consistent with higher levels of pollution, and lower at Mallorca (Balearic Islands). Varying responses were obtained for the other antioxidant enzymes. Glutathione S-transferase (GST), a detoxification enzyme, was also measured in the livers of red mullet fish and found to be significantly higher a t Cortiou than a t the other locations studied. Chemical measurement of PAH in surface sediment indicated the pyrolytic orlgln of this contaminant for all stations except hdilazzo (petroleum origin). Detection of DNA adducts as a bioindicator of exposure to carcinogenic substances was tested according to 2 complementary assay techniques: enzymelinked lmmunosorbent assay (ELISA) and 32P-postlabeling. ELISA revealed maximal quantities of PAH-DNA at Barcelona (15 adducts per 10' nucleotides), Cap Finale (Corsica) (20.8) and Milaxzo (15.5). The richest adduct profiles were detected by the 3 2~ method a t Antibes (France), Santa Ponza (Balearic Islands), Milazzo and C a p Finale, with a maximum of 6.2 adducts per 10' nucleotides at Milazzo. This multlmarker approach showed that pollutant exposure levels vaned according to site. With a sedimentary PAH profile apparently resulting from petroleum pollution, the Milazzo station had the greatest quantity of DNA adducts and the highest inductions of EROD actlvity and AChE inhib~tions in M. barbatus and S, hepatus.
Summary Cigarette smoking has been associated with increased risk of hepatocellular carcinoma (HCC) in some epidemiological studies. Cytochrome P450 1A1 (CYP1A1) is involved in the biotransformation of tobacco-derived polycyclic aromatic hydrocarbons (PAHs) into carcinogenic metabolites. The aim of this study was to determine whether CYP1A1 polymorphisms were related to HCC risk among chronic hepatitis B virus (HBV) carriers. Genotypic variants of CYP1A1 were determined using polymerase chain reaction in 81 incident cases of HCC and 409 controls nested in a cohort study of 4841 male chronic HBV carriers. No overall association between CYP1A1 genotypes and HCC was observed. The presence of the MspI (odds ratio (OR) 3.15, P = 0.0196) or Ile-Val (OR 1.99, P = 0.0855) variant allele of CYP1A1 increased HCC risk among smokers, but posed no increased risk among non-smokers. The smoking-related HCC risk was most pronounced among those who had a susceptible allele of the CYP1A1 and a deficient genotype of glutathione S-transferase M1, which detoxifies PAH electrophilic metabolites produced by CYP1A1. In the absence of the Ile-Val variant allele, the MspI polymorphism was still associated with smoking-related HCC. This study suggests that tobacco-derived PAHs play a role in HCC risk among chronic HBV carriers, and CYP1A1 polymorphism is an important modulator of the hepatocarcinogenic effect of PAHs. The MspI and Ile-Val polymorphisms of CYP1A1 may have different mechanisms for increasing susceptibility to smoking-related HCC.
Dietary exposure to aflatoxins is one of the major risk factors for hepatocellular carcinoma. Individual susceptibility to aflatoxin-induced hepatocarcinogenesis may be modulated by both genetic and environmental factors affecting metabolism. A cross-sectional study was performed to evaluate determinants of the formation of aflatoxin covalently bound to albumin (AFB 1 -albumin adducts). A total of 474 subjects who were free of liver cancer and cirrhosis and were initially selected as controls for previous case -control studies of aflatoxin-induced hepatocarcinogenesis in Taiwan, were employed in this study. Aflatoxin-albumin adducts were determined by competitive enzyme-linked immunosorbent assay, hepatitis B surface antigen and antibodies to hepatitis C virus by enzyme immunoassay, as well as genotypes of glutathione S-transferase M1-1 and T1-1 by polymerase chain reaction. The detection rate of AFB 1 -albumin adducts was significantly higher in males (42.5%) than in females (21.6%) (multivariate-adjusted odds ratio=2.6, 95% confidence interval=1.4 -5.0). The formation of detectable albumin adducts was moderately higher in hepatitis B surface antigen carriers (42.8%) than in non-carriers (36.6%) (multivariate-adjusted odds ratio=1.4, 95% confidence interval=1.0 -2.1). In addition, the detection rate of AFB 1 -albumin adducts tended to increase with the increasing number of null genotypes of glutathione S-transferase M1-1 and glutathione Stransferase T1-1. In conclusion, this cross-sectional study has assessed the relative contributions of environmental exposure and host susceptibility factors in the formation of AFB 1 -albumin adducts in a well characterised Chinese adult population. This study further emphasises the necessity to reduce aflatoxin exposure in people living in an area endemic for chronic hepatitis B virus infection.
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