Molecular epidemiology of human cancer and DNA adducts

The emerging field of molecular epidemiology is based on the detection of biological markers of human chronic disease with environmental components for the purpose of identifying its causes and outcomes.912 Identification of human carcinogens is considered most accurate when supported by cancer epidemiology data.13 The biomarkers used in the molecular epidemiology of human cancer include specific changes at the gene and chromosome level (polymorphisms, mutations and cytogenetic alterations),...

Assessment of DNA repair capacity in human cells

This year, over 800,000 people in the United States will be diagnosed with skin cancer, the most common form of cancer. There are large amounts of epidemiological data that indicate that sun exposure causes genetic changes in skin cells leading to basal cell carcinoma or squamous cell carcinoma. UV light-induced photoproducts are repaired by NER in which a complex series of over 30 proteins work together to remove the DNA lesion. Several photosensitive human disorders have been associated with...

Mitochondrial DNA damage as a biomarker of oxidative stress

One of the most ubiquitous DNA damaging agents is oxidative stress, an endogenous DNA damaging agent generated by normal cellular respiration. During the formation of ATP, electrons flow down the electron chain complexes, which generate a proton-gradient that is harvested by complex V, ATPase synthase. The final acceptor of electrons is molecular oxygen which is reduced in a four-electron addition to water. However reactive oxygen products of one- and two-electron additions, superoxide and...

Biomarkers of genetic integrity or damage

Epidemiologic studies of large populations have demonstrated increased risk of certain congenital anomalies associated with various paternal occu-pations.90 Given the low background population frequency of even the most common anomalies, such studies require a population base of thousands of pregnancies in order to have a reasonable probability of detecting an increased risk. Numerous case-control studies of childhood cancers have found significant associations with paternal occupations and...

Exposure to POPs and other congeners

AHR-inactive III. Environmental A. Induced responses in human B. Incidence of breast Abstract Persistent organic pollutants (POPs) are typically lipophilic compounds that are resistant to environmental breakdown and preferentially bioconcentrate in fish, wildlife, and human tissues. Most POPs are haloge-nated hydrocarbons as are some of their phenolic metabolites, including polychlorinated biphenyls (PCBs), dibenzofuran (PCDFs), dibenzo-p-diox-ins (PCDDs), hydroxy-PCBs,...

BDNA repair capacity

Several variants are associated with altered DNA repair capacity. Spitzet al.,111 reported that variant alleles at amino acid residues 312 and 751 of ERCC2 (XPD) were associated with reduced repair capacity in lymphocytes from individuals in a lung cancer cohort. Being homozygous for a variant allele in either XPC or XPD was associated with reduced capacity to repair UV-induced DNA damage as assayed by the host reactivation assay in a cohort of healthy subjects (Q. Wei, pers. comm.). Not...

Multiplex phenotypes

A trait that is dependent on two or more genes is called polygenic, multifactorial, or a multiplex phenotype. Examples of a polygenic trait include height, obesity, blood pressure, coronary artery disease, asthma, diabetes mellitus, or the formation of the jaw during embryonic development. Mul tiplex phenotypes might also include some defined toxicity of an environmental agent (at a given exposure for a defined time). It is becoming increasingly clear that there is never really a simple...

Arsenic carcinogenesis

Arsenic is present in various forms in the environment. It is closely linked to several human diseases including blackfoot, diabetes, hypertension and cancers of the skin, lung, bladder and liver. Much research has shown that metabolism of arsenic increases the level of ROS.52 Wang et al.52 demonstrated that arsenite enhances production of ROS and causes ROS-mediated apoptosis in Chinese hamster ovary cells and that antioxidants could prevent the ROS-mediated effects. N-acetyl-cysteine was...

Health effects of PCB exposure

These initial studies demonstrated clearly that Akwesasne Mohawks were exposed to PCBs, and that a major source of exposure was consumption of contaminated fish. We have continued a collaborative project with this population over the past 6 years, now investigating health effects in children born at the time when fish consumption was common, and in adults. The results of these studies have not yet been completed, since data collection has ended less than one year ago. However, we have...

Inhaled mercury vapor

Markers of dose to the brain present a special problem in the case of inhaled mercury vapor. The vapor is a monatomic gas that is highly diffusible and lipid soluble. It can penetrate cell membranes with ease. It diffuses from the alveolar regions in the lung to the blood stream from which it enters all cells and tissues. It passes across the blood-brain barrier (Figure 15.2). Once inside the cell, it is subject to rapid oxidation to mercuric mercury (Hg++) which is believed to be the proximate...

Reproductive hormone profiles

The profile recommended by NIOSH to evaluate endocrine dysfunction associated with reproductive toxicity consists of serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and prolactin. Because of the pulsatile secretion of LH, testosterone and to a much lesser extent FSH, as well as the variability in the evaluation of reproductive hormones, it is recommended that three blood samples be drawn at set intervals in the early morning and the results...

Lung cancer incidence predisposition and environment

Lung cancer is the paradigm of an environmentally induced disease. It is estimated that there will be 169,400 new cases and an estimated 154,900 deaths accounting for 28 of cancer-related deaths in the United States in 2002.1 The prognosis for lung cancer remains poor, with a 13 overall 5-year relative survival rate. About 87 of the cancer cases are attributed to cigarette smoking and the relative risk for lung cancer in current smokers compared with those who have never smoked is up to 20-fold...

Tamoxifen is a carcinogen

The antiestrogen tamoxifen is widely used as first-line endocrine therapy for breast cancer patients more than 500,000 women in the United States are currently being treated with this drug.5 A randomized clinical trial designed for healthy women at high risk of developing this disease showed that therapeutic doses of tamoxifen reduced the risk of invasive breast cancer by approximately 50 .6 Subsequently, tamoxifen was approved in 1998 for use as a chemopreventive agent. Unfortunately, the use...

Tier 1 CALUX bioassay

The first tier screening bioassay is based on the biochemical mechanism of action of TCDD (Figure 33.1) and related HAHs and involves the Ah receptor (AhR), a ligand-dependent transcription factor which can activate the expression of target genes specifically in response to these chemicals.6 Following high-affinity binding of TCDD HAH, the cytosolic ligand-AhR complex undergoes transformation during which it translocates into the nucleus, dissociates from its protein complex, and following its...

Positron emission tomography imaging peripheral benzodiazepine receptors in the living brain

Advances in positron emission tomography (PET) have made possible non-invasive visualization and measurement of specific biochemical processes in the living brain with exquisite resolution. A detailed technical description of this technique is beyond the scope of this chapter.6667 Briefly, PET is based on the use of short-lived (minutes), positron-emitting radioisotopes (carbon-11, fluorine-18) for labeling organic molecules or drugs which are part of specific biochemical reactions or interact...

Chapter thirtyfive

University-community partnership for the study of environmental contamination at Akwesasne David O. Carpenter, Alice Tarbell, Edward Fitzgerald, Michael J. Kadlec, David O'Hehir, and Brian Bush II. Polychlorinated A. PCBs in soils, sediments, and B. PCB levels in fish, game, and C. PCBs in D. PCBs in Akwesasne III. Health effects of PCB IV. University-community Abstract The Mohawk Nation at Akwesasne is a Native American community of about 12,000 persons who reside at the juncture of New York,...

Capacitance cytometry

The electrical properties of biological cells are of great interest, as they can provide opportunities to develop novel, rapid assays for disease7 and integrated hybrid chips for electronics.8,9 Previous electrical studies of cells have focused on external macroscopic properties, such as cell membrane responses or volume, and have primarily reflected those of large ensembles of cells.10,11 In this section, we describe capacitance cytometry, which we have recently developed and allows us to...

Repair of DNA damage

To counter the impact of this extensive damage to the DNA that is constantly occurring in each cell, organisms have developed several, generally nonredundant, pathways for repairing different DNA lesions. Nucleotide excision repair (NER) removes photoproducts induced in DNA by exposure to UV radiation and also the bulky DNA adducts formed following exposure to a multitude of chemicals.28-32 The NER pathway involves more than 30 proteins, at least 13 of which form a single multiprotein complex....

A NAcetylation NAT2

Differences in this metabolism phenotype were first identified in the late 1940s when patients who converted to a positive tuberculin test were routinely treated with isoniazid. A high incidence of peripheral neuropathy was found among those taking isoniazid. By giving isoniazid and measuring plasma levels 6 hours later (Figure 4.1), individuals could be phenotyped as slow acetylators (r, clearing the drug slowly) or rapid acetylators (R, clearing the drug quickly). The slow phenotype is...

Porphyria cutanea tarda and CYP1A2

CYP1A2 metabolizes many environmental aromatic amine procarcinogens, including tobacco smoke-specific dibenzo c,g carbazole and nitrosamines such as 4- methylnitrosamino - 1- 3-pyridyl -1-butanone NNK and numerous food-derived heterocyclic amines generated from the frying of meat and fish. There is suggestive evidence of an association between diets of fried meats and certain forms of cancer. Metabolic activation of these environmental chemicals, largely by CYP1A2, appears to be responsible for...