Arthur Chiu

Review of Chromium (VI) Apoptosis, Cell-Cycle-Arrest, and Carcinogenesis

Hexavalent chromium combines with glutathione in chloride intracellular channel carrier to form tetravalent and pentavalent chromium in plasma and organelle membranes. It also combines with NADH/NADPH to form pentavalent chromium in mitochondria. Tetravalent- and pentavalent- chromium (directly and indirectly) mediated DNA double strand breaks activate DNA damage signaling sensors: DNA-dependent-protein-kinase signals p53-dependent intrinsic mitochondrial apoptosis, and ataxia-telangiectasia-mutated and ataxia-telangiectasia-Rad3-related signal cell-arrest for DNA repair. Tetravalent chromium may be the most potent species since it causes DNA breaks and somatic recombination, but not apoptosis. Upon further failure of apoptosis and senescence/DNA-repair, damaged cells may become immortal with loss-of-heterozygosity and genetic plasticity.

Epidemiologic Studies of PCB Congener Profiles in North American Fish Consuming Populations

Abstract Long range atmospheric and stream transport and oceanic currents drive the ecologic process of PCB deposition in the abiotic environment. In contrast short range transport via bioaccumulation–biomagnification up the food chain determines PCB congener profiles and concentrations and their adverse effects in biological organisms. Two research approaches to congeners, with potential to associate specific adverse human health effects with PCB concentrations in indigenous small populations, are summarized in this study. The field epidemiologic approach includes giving questionnaires to target population groups in conjunction with sampling for PCBs (and selected persistent organic pollutants and metals), in foods purchased or hunted and collected by Inuit peoples. Direct determination of contaminant levels in food sources and among individuals in selected comparative subpopulations is also presented. #Disclaimer: The opinions and conclusions of this article are those of the individual authors and do not necessarily reflect those of their affiliated institutions.

Chromium-mediated apoptosis: involvement of DNA-dependent protein kinase (DNA-PK) and differential induction of p53 target genes

Cellular stress and DNA damage up-regulate and activate p53, fundamental for cell cycle control, senescence, DNA repair and apoptosis. The specific mechanism(s) that determine whether p53-dependent cell cycle arrest or p53-dependent apoptosis prevails in response to specific DNA damage are poorly understood. In this study, we investigated two types of DNA damage, chromium treatment and gamma irradiation (IR) that induced similar levels of p53, but that mediated two distinct p53-dependent cell fates. Chromium exposure induced a robust DNA-dependent protein kinase (DNA-PK)-mediated apoptotic response that was accompanied by the rapid loss of the cyclin-dependent kinase inhibitor 1A (p21) protein, whereas IR treatment-induced cell cycle arrests that was supported by the rapid induction of p21. Inhibition of DNA-PK effectively blocked chromium-, but not IR-induced p53 stabilization and activation. In contrast, inhibition of ATM and ATR by caffeine had the inverse effect of blocking IR-, but not chromium-induced p53 stabilization and activation. Chromium exposure ablated p21 transcription but PUMA and Bax transcription was significantly enhanced compared to non-damaged cells. In contrast, IR treatment triggered significant p21 mRNA synthesis in addition to PUMA and Bax mRNA production. While chromium treatment enhanced the binding of p53 and RNA polymerase II (RNA Pol II) to both the p21 and PUMA promoters, RNA Pol II elongation was only observed along the PUMA gene and not the p21 gene. In contrast, following IR treatment, RNA Pol II elongation was observed on both p21 and PUMA. Chromium-induced apoptosis therefore involves DNA-PK-mediated p53 activation followed by preferential transcription of pro-apoptotic PUMA over anti-apoptotic p21 genes.

Genetic and cellular mechanisms in chromium and nickel carcinogenesis considering epidemiologic findings.

Genetic and environmental interactions determine cancer risks but some cancer incidence is primarily a result of inherited genetic deficits alone. Most cancers have an occupational, viral, nutritional, behavioral or iatrogenic etiology. Cancer can sometimes be controlled through broad public health interventions including industrial hygiene and engineering controls. Chromium and nickel are two human carcinogens associated with industrial exposures where public health measures apparently work. Carcinogenic mechanisms of these metals are examined by electron-spin-resonance-spectroscopy and somatic-mutation-and-recombination in Drosophila melanogaster in this report. Both metals primarily affect initiation processes in cancer development suggesting important theoretical approaches to prevention and followup.

INHALATION EXPOSURE TO VOLATILE CHEMICALS IN DRINKING WATER

Inhalation of volatile chemicals released during household water use is a recognized exposure pathway. Models previously developed to estimate inhalation exposure to radon gas, radon progeny, and volatile organic compounds (VOCs) were limited in their ability to predict exposure to compounds of low volatility due to a lack of appropriate experimental data. Recently, a comprehensive series of experimental studies has been completed in which mass-transfer coefficients for a shower, bath, faucet, washing machine, and dishwasher have been measured, making more detailed and accurate predictions possible. In this paper, the theoretical basis for mass transfer between water and air is reviewed and then extended to include the pH-dependent transfer of volatile compounds that participate in rapid acid/base reactions. This class of compound has not previously been considered in exposure assessment models. The evolution of inhalation exposure models is briefly reviewed and an improved version is developed. Sample calculations are made demonstrating the influence of both low volatility and pH on inhalation exposure. The paper concludes with illustrative examples assessing the toxicological implications of exposure to radon and hydrogen cyanide. The analysis confirms that inhalation is an important exposure pathway for waterborne chemicals.

Effects and mechanisms of PCB ecotoxicity in food chains: Algae fish seal polar bear 1

Abstract Wildlife populations are adversely affected in polluted environments. Nevertheless, a cause‐and‐effect relationship between excessive exposure to chlorinated hydrocarbons and induction of pathologic disorders in animals, is difficult to demonstrate without verification from experiments following the rationale of Kochs postulates. Deleterious effects of chlorinated chemicals such as DDT on songbird reproduction, as demonstrated by the clutch size of eggs in a nest, however, is an example, where exposure and causation are apparent. With amelioration of DDT pollution, clutch size increases, and the cause‐and‐effect relationship is established. Similar examples of exposure to DDT and PCBs inducing reproductive disorders and endocrine disruption among marine mammals have been documented in industrialized nations of northern Europe and in the upper latitudes of the Northern Hemisphere. Population declines in ringed, grey and harbor seals are apparently due to a rapid decrease in their rates of reproduction1. These latter observations are best interpreted in light of experiments conducted by Reijnders2. Reijnders exposed harbor seals to relatively high dietary levels of PCBs and induced PCB‐blood‐lipids among seals to an average of 25 mg/kg compared to 10 mg/kg among controls. The treated seals had a significantly reduced reproductive rate. A relationship between increased PCB‐blood‐levels in vivo and the decrease in reproductive rates in this experiment is highly instructive for interpreting the decline of fertility in seal populations in polluted Baltic Sea waters. These linked observations are dependent upon demonstration of pathologic mechanisms associated with occlusion and stenosis of the uterine lumen among affected females in seal populations. PCB congeners apparently disrupt endocrine‐system‐functions leading to, or associated with, increases in endometriosis, fetal abortion, glomerulonephropathies and osteoporosis. This observation is further highlighted by Reijnders experiment, which closely replicated the range of PCB concentrations found in seal populations living in a variety of PCB polluted waters. Various PCB congeners differentially accumulate in brain, liver and adipose tissues in young and old seals. Further research of PCB toxic effects on organ systems of these animals and other species is thus indicated. This report, then, examines the process of PCB bioaccumulation within the marine food chain from fish to seals, whales, other marine mammals and to polar bears. Environmental toxic pollutants affect animals within the food chain in different ways but ultimately they affect humans as well.

Proliferative hepatocellular lesions of the rat: review and future use in risk assessment.

Background. When liver carcinogens are administered to rats, there is an increase in the frequency of certain morphological lesions and often a chronology in their formation. Generally foci of cellular alteration are first to appear, then neoplastic nodules, and finally carcinomas are noted in the livers of the rats. This time sequence suggests an interpretation of the carcinogenic process in which foci are a precursor stage in the development of neoplastic nodules, which in turn are precursors of carcinomas. However, under certain circumstances, if carcinogen administration ceases, many foci and neoplastic nodules disappear, and the formation of carcinomas occurs at a low frequency. Thus, an alternative interpretation is that foci and neoplastic nodules may be independent of carcinoma development. Because of these general findings, it is difficult to evaluate the significance of increases in lesions in long-term tests in rats. Since there is no certain scientific knowledge or consensus about the biological significance of liver nodules, the EPA needs a policy for the interpretation of rat carcinogen bioassays in which liver nodules are an end point.

Activation of a procarcinogen by reduction: Cr6+→Cr5+→Cr4+→Cr3+ a case study by electron spin resonance (ESR/PMR)∗

Abstract Chromate is a human carcinogen. Since it does not form a covalent DNA adduct in vitro under physiological conditions, and is not mutagenic in vitro in the presence of cytochrome P450 preparations from liver, reduction of Cr6+ by cellular reductants to lower oxidation states such as Cr5+, Cr4+ is considered to be a critical step in the mechanism of carcinogenesis. Long‐lived paramagnetic chromium species, Cr5+, Cr4+, Cr3+ are formed in the presence of coenzymes such as NAD(P)H, GSH, and cytochromes. These anionic complexes of reduced chromium are considered potential “penultimate” carcinogens. Various in vitro and in vivo studies from our group have demonstrated the formation of these ionic species using a modified paramagnetic spectroscopy approach. In this review, information is provided on the half‐lives of formation and decay, free energy changes, atomic structures and reaction mechanisms of these compounds in situ, in vivo and in vitro, at the molecular, cellular and organismic levels. Hydrox...

Environmental carcinogenesis and biotechnology

Numerous environmental and host factors, some of which are known and some unknown, contribute to cancer development. While data and studies abound, our current understanding of the relation between cancer and the environment is still very limited. Understanding environmental carcinogenesis is critical to its effective management. Biotechnology has revolutionalized the study of biological and biomedical sciences. This minireview provides an overview of environmental carcinogenesis with emphasis on the contributions and prospects of biotechnology in advancing an understanding of environmental carcinogenesis for its prevention and intervention.