• Uptake of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by Moldovan children.

      Stepanov, Irina; Hecht, Stephen S.; Duca, Gheorghe; Mardari, Igor (2006-01)
      The evidence of an association between childhood exposure to environmental tobacco smoke (ETS) and an increased risk of lung cancer is inconsistent. However, taking into account the existing association between lung cancer and adulthood ETS exposure, it is plausible that children exposed to ETS also would be at risk of developing lung cancer later in life. In this study, we investigated the uptake by Moldovan children of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by measuring total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the sum of the NNK metabolites, NNAL, and its O-glucuronide and N-glucuronide (NNAL-Glucs) in urine. We also measured urinary cotinine and its glucuronide (total cotinine). Total NNAL was detected in 69 of 80 samples, including those that were low in cotinine (<5 ng/mL). The mean+/- SD level of total NNAL (0.09+/- 0.077 pmol/mL) was comparable with those observed in previous studies of children and adults exposed to ETS. Total NNAL correlated with total cotinine (r=0.8, P<0.0001). The mean+/- SD levels of total NNAL and total cotinine were higher in children who were exposed to ETS (0.1+/- 0.08 and 109+/- 126 pmol/mL, respectively) than in those who were classified as unexposed to ETS based on questionnaire data (0.049+/- 0.016 pmol/mL and 0.043+/- 0.040 nmol/mL). The results of this study for the first time show widespread and considerable uptake of nicotine and the tobacco-specific lung carcinogen NNK in Moldovan children. These results should be useful in heightening the awareness of the dangers of smoking and ETS exposure in this eastern European country.
    • Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer.

      Nagar, S.; Remmel, R. P. (2006-03-13)
      The uridine diphosphoglucuronosyltransferases (UGTs) belong to a superfamily of enzymes that catalyse the glucuronidation of numerous endobiotics and xenobiotics. Several human hepatic and extrahepatic UGT isozymes have been characterized with respect to their substrate specificity, tissue expression and gene structure. Genetic polymorphisms have been identified for almost all the UGT family members. A wide variety of anticancer drugs, dietary chemopreventives and carcinogens are known to be conjugated by members of both UGT1A and UGT2B subfamilies. This review examines in detail each UGT isozyme known to be associated with cancer and carcinogenesis. The cancer-related substrates for several UGTs are summarized, and the functionally relevant genetic polymorphisms of UGTs are reviewed. A number of genotype-phenotype association studies have been carried out to characterize the role of UGT pharmacogenetics in several types of cancer, and these examples are discussed here. In summary, this review focuses on the role of the human UGT genetic polymorphisms in carcinogenesis, chemoprevention and cancer risk.
    • Urinary 1-hydroxypyrene as a biomarker of PAH exposure in 3-year-old Ukrainian children.

      Mucha, Amy Pelka; Hryhorczuk, Daniel; Serdyuk, Andrij; Nakonechny, Joseph; Zvinchuk, Alexander; Erdal, Serap; Caudill, Motria; Scheff, Peter; Lukyanova, Elena; Shkiryak-Nyzhnyk, Zoreslava; et al. (2006-04)
      Urinary 1-hydroxypyrene (1-OHP) is a biomarker of polycyclic aromatic hydrocarbon (PAH) exposure. We measured urinary 1-OHP in 48 children 3 years of age in Mariupol, Ukraine, who lived near a steel mill and coking facility and compared these with 1-OHP concentrations measured in 42 children of the same age living in the capital city of Kiev, Ukraine. Children living in Mariupol had significantly higher urinary 1-OHP and creatinine-adjusted urinary 1-OHP than did children living in Kiev (adjusted: 0.69 vs. 0.34 micromol/mol creatinine, p < 0.001; unadjusted: 0.42 vs. 0.30 ng/mL, p = 0.002). Combined, children in both cities exposed to environmental tobacco smoke in their homes had higher 1-OHP than did children not exposed (0.61 vs. 0.42 micromol/mol creatinine; p = 0.04; p = 0.07 after adjusting for city). In addition, no significant differences were seen with sex of the children. Our sample of children in Mariupol has the highest reported mean urinary 1-OHP concentrations in children studied to date, most likely due to their proximity to a large industrial point source of PAHs.
    • Urinary biomarkers of 1,3-butadiene in environmental settings using liquid chromatography isotope dilution tandem mass spectrometry.

      Sapkota, Amir; Halden, Rolf U.; Dominici, Francesca; Groopman, John D.; Buckley, Timothy J. (2006-03-10)
      Although, 1,3-butadiene is a known human carcinogen emitted from mobile sources, little is known about traffic-related human exposure to this toxicant. This pilot study was designed to characterize traffic-related environmental exposure to 1,3-butadiene and evaluate its urinary mercapturic acids as biomarkers of exposure in these settings. Personal air samples and multiple urine samples were collected on two separate occasions from three groups of individuals that differed by spatial proximity as well as intensity of traffic: (i) toll collectors, (ii) urban-weekday and (iii) suburban-weekend group. Air samples were analyzed using thermal desorption followed by GC/MS and urine samples were analyzed using isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) for two mercapturic acids of 1,3-butadiene: monohydroxy-3-butenyl mercapturic acid (MHBMA) and 1,2-dihydroxybutyl mercapturic acid (DHBMA). Exposure differed between groups (p<0.05) with median values of 2.38, 1.62 and 0.88 microg/m(3) for toll collectors, the urban-weekday group and the suburban-weekend group, respectively. A refined ID-LC-MS/MS method enabled detection of MHBMA, previously detected only in occupational settings, with high frequency. MHBMA and DHBMA were detected in 95 and 100% of urine samples at levels (mean+/-S.D.) of 9.7+/-9.5, 6.0+/-4.3 and 6.8+/-2.6 ng/mL for MHBMA and 378+/-196, 258+/-133 and 306+/-242 ng/mL for DHBMA for the three different groups, respectively. Mean biomarker levels were higher among the toll collectors compared to the other two groups, however, the differences were not statistically significant (p>0.05). This study is the first to evaluate 1,3-butadiene biomarkers for subtle differences in environmental exposures. However, additional research will be required to ascertain whether the lack of statistical association observed here is real or attributable to unexpectedly small differences in exposure between groups (<1 microg/m(3)), non-specificity of the biomarker at low exposure, and/or small sample size.
    • Using biologic markers in blood to assess exposure to multiple environmental chemicals for inner-city children 3-6 years of age.

      Sexton, Ken; Adgate, John L.; Fredrickson, Ann L.; Ryan, Andrew D.; Needham, Larry L.; Ashley, David L. (2006-03)
      We assessed concurrent exposure to a mixture of > 50 environmental chemicals by measuring the chemicals or their metabolites in the blood of 43 ethnically diverse children (3-6 years of age) from a socioeconomically disadvantaged neighborhood in Minneapolis. Over a 2-year period, additional samples were collected every 6-12 months from as many children as possible. We analyzed blood samples for 11 volatile organic compounds (VOCs), 2 heavy metals (lead and mercury, 11 organochlorine (OC) pesticides or related compounds, and 30 polychlorinated biphenyl (PCB) congeners. The evidence suggests that numerous VOCs originated from common sources, as did many PCBs. Longitudinal measurements indicate that between-child variance was greater than within-child variance for two VOCs (benzene, toluene), for both heavy metals (Pb, Hg), for all detectable OC pesticides, and for 15 of the measured PCB congeners (74, 99, 101, 118, 138-158, 146, 153, 156, 170, 178, 180, 187, 189, 194, 195). Despite the relatively small sample size, highest measured blood levels of 1,4-dichlorobenzene, styrene, m-/p-xylene, Pb, Hg, heptachlor epoxide, oxychlordane, dichlorodiphenyldichloroethene (p,p -DDE), trans-nonachlor, and PCB congeners 74, 99, 105, 118, 138, 146, 153, 156, 170, and 180 were comparable with or higher than 95th percentile measurements of older children and adults from national surveys. Results demonstrate that cumulative exposures to multiple environmental carcinogens and neurotoxins can be comparatively high for children from a poor inner-city neighborhood.
    • Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action.

      Zhang, Yuesheng; Yao, Song; Li, Jun (2006-02)
      Many isothiocyanates (ITC), which are available to human subjects mainly through consumption of cruciferous vegetables, demonstrate strong cancer-preventive activity in animal models. Human studies also show an inverse association between consumption of ITC and risk of cancer in several organs. Whereas earlier studies primarily focused on the ability of ITC to inhibit carcinogen-activating enzymes and induce carcinogen-detoxifying enzymes, more recent investigations have shown that ITC inhibit the proliferation of tumour cells both in vitro and in vivo by inducing apoptosis and arresting cell cycle progression. ITC cause acute cellular stress, which may be the initiating event for these effects. These findings shed new light on the mechanism of action of ITC and indicate that ITC may be useful both as cancer-preventive and therapeutic agents. ITC activate caspase 9-mediated apoptosis, apparently resulting from mitochondrial damage, and also activate caspase 8, but the mechanism remains to be defined. Cell cycle arrest caused by ITC occurs mainly in the G2/M phase, and both the G2 and M phases are targetted; critical G2-phase regulators, including cyclin B1, cell division cycle (Cdc) 2 and Cdc25C, are down regulated or inhibited, and tubulin polymerization and spindle assembly are disrupted. Moreover, ITC are metabolized in vivo through the mercapturic acid pathway, giving rise to thiol conjugates (dithiocarbamates). Studies show that these dithiocarbamates are similar to their parent ITC in exerting anti-proliferative activity. Taken together, dietary ITC are highly-promising anti-cancer agents, capable of targetting multiple cellular components that are important for tumour cell survival and proliferation.
    • Vitamin D physiology.

      Lips, P. (2006-09)
      Vitamin D3 is synthesized in the skin during summer under the influence of ultraviolet light of the sun, or it is obtained from food, especially fatty fish. After hydroxylation in the liver into 25-hydroxyvitamin D (25(OH)D) and kidney into 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite can enter the cell, bind to the vitamin D-receptor and subsequently to a responsive gene such as that of calcium binding protein. After transcription and translation the protein is formed, e.g. osteocalcin or calcium binding protein. The calcium binding protein mediates calcium absorption from the gut. The production of 1,25(OH)2D is stimulated by parathyroid hormone (PTH) and decreased by calcium. Risk factors for vitamin D deficiency are premature birth, skin pigmentation, low sunshine exposure, obesity, malabsorption and advanced age. Risk groups are immigrants and the elderly. Vitamin D status is dependent upon sunshine exposure but within Europe, serum 25(OH)D levels are higher in Northern than in Southern European countries. Severe vitamin D deficiency causes rickets or osteomalacia, where the new bone, the osteoid, is not mineralized. Less severe vitamin D deficiency causes an increase of serum PTH leading to bone resorption, osteoporosis and fractures. A negative relationship exists between serum 25(OH)D and serum PTH. The threshold of serum 25(OH)D, where serum PTH starts to rise is about 75nmol/l according to most surveys. Vitamin D supplementation to vitamin D-deficient elderly suppresses serum PTH, increases bone mineral density and may decrease fracture incidence especially in nursing home residents. The effects of 1,25(OH)2D and the vitamin D receptor have been investigated in patients with genetic defects of vitamin D metabolism and in knock-out mouse models. These experiments have demonstrated that for active calcium absorption, longitudinal bone growth and the activity of osteoblasts and osteoclasts both 1,25(OH)2D and the vitamin D receptor are essential. On the other side, bone mineralization can occur by high ambient calcium concentration, so by high doses of oral calcium or calcium infusion. The active metabolite 1,25(OH)2D has its effects through the vitamin D receptor leading to gene expression, e.g. the calcium binding protein or osteocalcin or through a plasma membrane receptor and second messengers such as cyclic AMP. The latter responses are very rapid and include the effects on the pancreas, vascular smooth muscle and monocytes. Muscle cells contain vitamin D receptor and several studies have demonstrated that serum 25(OH)D is related to physical performance. The active metabolite 1,25(OH)2D has an antiproliferative effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. Active calcium absorption from the gut depends on adequate formation of 1,25(OH)2D and an intact vitamin D receptor. Bone mineralization mainly depends on ambient calcium concentration. Vitamin D metabolites may play a role in the prevention of auto-immune disease and cancer.
    • The vitamin D questions: how much do you need and how should you get it?

      Wolpowitz, Deon; Gilchrest, Barbara A. (2006-02)
      UV radiation is a well-documented human carcinogen, indisputably linked to the current continued increased rate of skin cancer. UV radiation is also responsible for cutaneous synthesis of vitamin (vit) D3, a substance that is then sequentially hydroxylated in the liver and kidney to yield 1,25(OH)2 vit D, a hormone critical for calcium homeostasis and skeletal maintenance. Because the UV action spectra for DNA damage leading to skin cancer and for vit D photosynthesis are virtually identical, the harmful and beneficial effects of UV irradiation are inseparable. This has given rise to the argument that sun avoidance, with a goal of skin cancer prevention, may compromise vit D sufficiency. Public interest in this matter has been heightened in recent years by multiple studies correlating the level of 25-OH vit D, the readily measurable "storage" precursor form of the vit, with a variety of benefits separate from skeletal health. Although the studies are of variable quality and all alleged treatment benefits are based on dietary supplementation with vit D, not on increased sun exposure, they have been interpreted by some as support for advocating increased sun exposure of the public at large. The goal of this review is to provide a detailed, balanced, and referenced discussion of the complex literature underlying the current popular interest in vit D and sun exposure for the purpose of increasing vit D photosynthesis. We review the nomenclature, metabolism, and established functions of vit D; the evidence supporting the less well-established but purported vit D effects; the concept of vit D insufficiency; populations at risk for vit D deficiency; and finally the risk/benefit of obtaining vit D from cutaneous photosynthesis versus diet or supplementation.
    • Vitamin D receptor gene polymorphisms, dietary promotion of insulin resistance, and colon and rectal cancer.

      Murtaugh, Maureen A.; Sweeney, Carol; Ma, Khe-Ni; Potter, John D.; Caan, Bette J.; Wolff, Roger K.; Slattery, Martha L. (2006)
      Modifiable risk factors in colorectal cancer etiology and their interactions with genetic susceptibility are of particular interest. Functional vitamin D receptor (VDR) gene polymorphisms may influence carcinogenesis through modification of cell growth, protection from oxidative stress, cell-cell matrix effects, or insulin and insulin-like growth factor pathways. We investigated interactions between foods (dairy products, red and processed meat, and whole and refined grains) and dietary patterns (sucrose-to-fiber ratio and glycemic index) associated with insulin resistance with the FokI polymorphism of the VDR gene and colon and rectal cancer risk. Data (diet, anthropometrics, and lifestyle) and DNA came from case-control studies of colon (1,698 cases and 1,861 controls) and rectal cancer (752 cases and 960 controls) in northern California, Utah, and the Twin Cities metropolitan area, Minnesota (colon cancer study only).Unconditional logistic regression models were adjusted for smoking, race, sex, age, body mass index, physical activity, energy intake, dietary fiber, and calcium. The lowest colon cancer risk was observed with the Ff/ff FokI genotypes and a low sucrose-to-fiber ratio. Rectal cancer risk decreased with greater consumption of dairy products and increased with red or processed meat consumption and the FF genotype. Modifiable dietary risk factors may be differentially important among individuals by VDR genotype and may act through the insulin pathway to affect colon cancer risk and through fat, calcium, or other means to influence rectal cancer risk.
    • Zinc deficiency potentiates induction and progression of lingual and esophageal tumors in p53-deficient mice.

      Fong, Louise Y. Y.; Jiang, Yubao; Farber, John L. (2006-07)
      Upper aerodigestive tract (UADT) cancer, including oral and esophageal cancer, is an important cause of cancer deaths worldwide. Patients with UADT cancer are frequently zinc deficient (ZD) and show a loss of function of the pivotal tumor suppressor gene p53. The present study examined whether zinc deficiency in collaboration with p53 insufficiency (p53+/-) promotes lingual and esophageal tumorigenesis in mice exposed to low doses of the carcinogen 4-nitroquinoline 1-oxide. In wild-type mice, ZD significantly increased the incidence of lingual and esophageal tumors from 0% in zinc sufficient (ZS) ZS:p53+/+ mice to approximately 40%. On the p53+/- background, ZD:p53+/- mice had significantly greater tumor incidence and multiplicity than ZS:p53+/- and ZD:p53+/+ mice, with a high frequency of progression to malignancy. Sixty-nine and 31% of ZD:p53+/- lingual and esophageal tumors, respectively, were squamous cell carcinoma versus 19 and 0% of ZS:p53+/- tumors (tongue, P = 0.003; esophagus, P = 0.005). Immunohistochemical analysis revealed that the increased cellular proliferation observed in preneoplastic lingual and esophageal lesions, as well as invasive carcinomas, was accompanied by overexpression of cytokeratin 14, cyclooxygenase-2 and metallothionein. In summary, a new UADT cancer model is developed in ZD:p53+/- mouse that recapitulates aspects of the human cancer and provides opportunities to probe the genetic changes intrinsic to UADT carcinogenesis and to test strategies for prevention and reversal of this deadly cancer.