Authors:K.T. Bogen Pages: 1 - 53 Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): K.T. Bogen The somatic mutation theory of tumorigenesis predicts that increased tumor risks posed by chronic, low-level exposures to mutagenic chemical carcinogens have linear-no-threshold low-dose dose–response (LDDR) relationships. A recently proposed alternative, dysregulated adaptive hyperplasia (DAH) theory does not imply this expectation, positing instead that tissue-specific tumors arise most efficiently only from a(ny) stem cell that (i) happens to be “activated” epigenetically (via a specific microRNA expression profile) to initiate and maintain a state of adaptive hyperplasia (AH) and (ii) additionally incurs a single, dysregulating mutation preventing transduction of the signal that normally terminates AH in that tissue (Bogen, 2013). Accumulating data support the hypothesis that sustained oxidative stress associated with elevated reactive oxygen species (ROS) triggers Keap1–Nrf2–ARE-mediated AH-stem-cell recruitment. Because Nrf2 activation is here demonstrated to have an unambiguously J-shaped LDDR, Nrf2 activation (even by chemical mutagens) could drive DAH-induced tumorigenesis. If so, despite experimental or epidemiologic evidence of increased tumor risk at higher doses, an Nrf2-driven DAH mechanism implies that sufficiently low-level chronic exposures to (even mutagenic) chemical carcinogens may typically increase tumor risk with a highly sublinear or threshold-like LDDR. This “Nrf2-DAH” theory is discussed in relation to key underlying concepts (stem cells, ROS, the Keap1–Nrf2–ARE pathway, inflammation, and autophagy), as well as experimental data that bear on this theory's plausibility and on its LDDR implications.
Authors:H. Li; Y. Peng; J. Zheng Pages: 55 - 97 Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): H. Li, Y. Peng, J. Zheng This chapter introduces the bioactivation and toxicity of furanoterpenoids, particularly their hepatotoxicity. It starts with a brief description of biosynthesis of furanoterpenoids, followed by mechanisms of metabolic activation of furan-containing compounds and the interactions of reactive metabolites of furanoids with proteins. A total of five furanoterpenoids, i.e., 4-ipomeanol, teucrin A, diosbulbin B, 8-epidiosbulbin E acetate, and toosendanin, are discussed as examples. The chapter covers (1) the natural source and toxicities of the furanoterpenoids; (2) identification of reactive metabolites and major cytochromes P450 involved in the metabolic activation of the furan-containing compounds; and (3) protein modifications induced by the reactive metabolites of the furanoids. It also describes a newly developed approach to screen potentially harmful furan-containing compounds from complicated mixtures.
Authors:A.G. Osman; A.G. Chittiboyina; I.A. Khan Pages: 99 - 137 Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): A.G. Osman, A.G. Chittiboyina, I.A. Khan Cancer poses a lingering health threat to the humans which is attributable to the shortage in availability of efficient curative agents. Several lines of epidemiological evidence as well as substantive in vivo and in vitro investigations have led to the emergence of the chemoprevention/cytoprotection concept. This principle denotes cell protection against development of cancer (carcinogenesis) through the regular intake of sufficient amounts of vegetables and fruits as these contain a myriad of phytochemicals which are discerned as the putative chemopreventive substances in plants. Alternatively, purified phytochemicals can be administered in daily doses. These plant constituents act by elevating the activity and/or increasing the gene expression of phase II detoxification enzymes and the antioxidant enzymes, collectively known as the cytoprotective enzymes. The first class of enzymes are capable of neutralizing the reactive electrophiles and the carcinogens via formation of water-soluble conjugates that are rapidly eliminated from the cells and excreted. The antioxidative enzymes act as scavengers for the reactive oxygen species and thus abrogate the oxidative stress which is a predisposition for carcinogenesis. Chemopreventive phytochemicals have been found among polyphenols and isothiocyanates, beside other phytochemical classes, including monophenolic acids, monoterpenes, sesquiterpenes, and triterpenes.
Authors:N.A. Saliba; J. Nassar; F. Hussein; D. El Kfoury; J. Nicolas; T. El Tal; R. Baalbaki Pages: 187 - 233 Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): N.A. Saliba, J. Nassar, F. Hussein, D. El Kfoury, J. Nicolas, T. El Tal, R. Baalbaki Scientific evidence has confirmed that air pollution is associated with several ailments and some particular toxic pollutants have caused cancer and death. Though anthropogenic emissions are increasing at a rate higher than data generation for hazard assessment, there is a lag in developing air quality regulations especially in developing countries. This chapter reviews the characteristics of some of the human carcinogens from VOC and SVOC chemical groups and PMs. It gives an in-depth look at the recent advances in the nano-PM size characterization and health studies and highlights the need for more studies to elucidate the mechanism that drives the toxicity of nanoparticles toward different organisms. This chapter also shows how scientific data can be put to use to estimate risk assessment and derive environmental laws that protect the public health. A look at the process led to proposing an environmental risk management system plausible for developing countries.
Authors:Heli Fan; Xiaohua Peng Pages: 235 - 292 Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): Heli Fan, Xiaohua Peng DNA interstrand cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. DNA cross-linking agents are used as anticancer agents, for DNA damage and repair study, for nucleic acid detection, and for construction of DNA nanomaterials. This chapter summarizes various novel methods and chemical reagents recently developed for inducing DNA ICL formation, the mechanisms involved for DNA cross-linking, and their applications. It starts by presenting photoinduced DNA ICL formation via [2+2] cycloaddition reaction, quinone methide, or carbocation formation. It then discusses novel DNA cross-linking agents activated by various chemical agents, including the arylboronate or boronic acid derivatives activated by hydrogen peroxide, silyl-protected bifunctional phenol derivatives triggered by fluoride, and phenyl selenides or furan analogs activated by oxidation reagents. General mechanisms involved formation of alkylating species, including quinone methide, nitrogen mustard, methide analogs, and enal formation. Enzyme-activated DNA cross-linking agents and their application for targeting cancer cells are also explained. By the end of the chapter, DNA ICL formation induced by “click” chemistry is highlighted.
Authors:K.A. Wilson; R.W. Kung; S.D. Wetmore Pages: 293 - 360 Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): K.A. Wilson, R.W. Kung, S.D. Wetmore Carcinogens arising from many sources (e.g., industrial agents, agricultural contaminants, environmental pollutants, food products, and medications) are known to attach to DNA to form nucleobase adducts. Experimental studies have shown that the chemical composition and biological consequences of these DNA lesions are widespread. This review highlights the judicious use of a range of computer modeling approaches to study previously unexplored molecular details of the cellular effects of DNA adducts and thereby aid our understanding of their toxicology. Emphasis is placed on the role of calculations in elucidating the structural implications of DNA adduct formation, as well as interactions between adducted DNA and critical cellular machinery (including enzymes involved in DNA replication and repair).
Authors:S. Swagatika; R.S. Tomar Pages: 361 - 389 Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): S. Swagatika, R.S. Tomar Many studies have demonstrated the significance of epigenetics in response to external and internal perturbations. Chromatin-associated transcription factors, posttranslational modifications that are also called epigenetic modifications of histone proteins and DNA, variants of histones, microRNAs, and ATP-dependent chromatin remodeling factors are the key epigenetic changes that regulate fundamental DNA-dependent biological processes. Disruption of epigenetic mechanisms is a major cause of diseases. Epigenetic-based therapies for the treatment of cancer and neurological disorders have also been started in clinical trials. Environment exposure has a great impact on modulation of epigenetics. Here in this review we describe the role of known epigenetic changes and discuss the consequences in response to toxic environmental molecules. Although the mechanism of epigenetic regulations is a complex process, due to advances in gene expression mechanisms, many molecules for modulation of epigenetics will hopefully be available for clinical use in the coming years.
Authors:Kostal Abstract: Publication date: 2016 Source:Advances in Molecular Toxicology, Volume 10 Author(s): J. Kostal This chapter outlines state-of-the art computational chemistry techniques that can be used to develop mechanistic descriptors for predictive models. For the reader to gain appreciation for the complexity of these calculations and to promote responsible usage of available computational software, basic principles of computational theory are presented along with simple guidelines for the nonexpert user. This chapter is organized around categorization of modeling approaches by level of theory (i.e., amount of rigor in the computational approach) and system size (i.e., extent of the biochemical system modeled). Simple examples are used throughout the text to illustrate the applicability of the outlined computational approaches to specific toxicological studies. Lastly, current practices in computational toxicology are contrasted with the concept of safer chemical design, and computational strategies are presented that can aid in de novo design of chemicals with minimal biological activity.
Authors:Kyung-A. Hwang; Kyung-Chul Choi Abstract: Publication date: 2015 Source:Advances in Molecular Toxicology, Volume 9 Author(s): Kyung-A. Hwang, Kyung-Chul Choi Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds present in the environment, which can interfere with hormone synthesis and normal physiological functions of male and female reproductive organs. Most EDCs tend to bind to steroid hormone receptors including the estrogen receptor (ER), progesterone receptor, and androgen receptor. As EDCs disrupt the actions of endogenous hormones, they may induce abnormal reproduction, stimulation of cancer growth, and dysfunction of neuronal and immune systems. Especially, xenoestrogens are classified as EDCs that have estrogenic activity and disrupt normal estrogen signaling mediated by ERs, and they have been emerging as another risk factor for estrogen-responsive cancers. In addition, phytoestrogens, which are biologically active phenolic compounds derived from plants and have structures similar to the principal mammalian estrogen, are also included in xenoestrogens. In this chapter, diverse effects of several chemical xenoestrogens and phytoestrogens in estrogen-responsive cancers including breast, ovarian, endometrial, and prostate cancers will be reviewed in relation with the underlying mechanisms which are all characterized by disturbances in ERs. This review may give insight for the etiology of estrogen-responsive cancers as well as chemopreventive potentials of phytoestrogens.
Authors:Walter Watson Abstract: Publication date: 2015 Source:Advances in Molecular Toxicology, Volume 9 Author(s): Walter H. Watson Environmental arsenic exposure is a world-wide human health problem. Arsenic is associated with a wide range of diseases, including skin lesions, cardiovascular disease, liver disease, and cancers of the skin, lung, liver, and bladder. Metabolism of arsenic yields a variety of molecular species, each of which can have different biological effects. This review will discuss the reactivity of different chemical forms of arsenic with distinct molecular targets of toxicological relevance. A particular emphasis will be given to studies investigating the roles of arsenic–sulfur interactions in the etiology of disease.
Authors:Khairul Islam; Qian Qian Wang Hua Naranmandura Abstract: Publication date: 2015 Source:Advances in Molecular Toxicology, Volume 9 Author(s): Khairul Islam, Qian Qian Wang, Hua Naranmandura Arsenic is a well-known poisonous substance and classed as being carcinogenic to humans. Epidemiological studies have indicated that arsenic is able to increase risk of cancers of lung, liver, bladder, and skin in human, and more the million people are suffering from the arsenic-contaminated drinking water in the world. Current research on the metabolism and biological effects of arsenic has deeply changed our understanding of the role of metabolism in modulation of toxicity and carcinogenicity of this metalloid. Historically, the enzymatic conversion of inorganic arsenic to mono- and dimethylated species has been considered a major mechanism for detoxification of inorganic arsenic. Some experimental evidence obtained from several laboratories suggests that biomethylation, particularly the production of methylated metabolites that contain trivalent arsenic, is a process that activates arsenic as a toxin and a carcinogen. In addition, the exact dose at which arsenic species induce tumors in vivo is still a major research question. Contrastingly, arsenic has recently been recognized as one of the most effective drugs for the treatment of acute promyelocytic leukemia. These contradictory effects of arsenic may be dose-dependent, associated with its distinctive metabolism, or correlated with its direct or indirect effects on different cellular pathways which may result in altered cellular functions and therefore necessitates more scientific investigation/research. In this chapter, we have mainly clarified the molecular mechanism of toxicity of arsenic based on arsenic metabolic pathway and its different metabolites need for better understanding of paradoxical effects of arsenic.
Authors:Ruchi Gera; Vikas Singh Anuj Sharma Debabrata Ghosh Abstract: Publication date: 2015 Source:Advances in Molecular Toxicology, Volume 9 Author(s): Ruchi Gera, Vikas Singh, Anuj K. Sharma, Debabrata Ghosh Exposure to different environmental chemicals like arsenic (As), cadmium (Cd), and lead (Pb) from natural and anthropogenic activity represents a threat to global human health. Human populations are exposed to these chemicals either through drinking water or through occupational exposure in various industries. Different organ systems are affected to varying degrees following exposure in a dose- and time-dependent manner. In this chapter, we will discuss specific human immune responses as well as immune responses of different mammalian model systems in exposure to three environmental chemicals, As, Cd, and Pb. Although there are conflicting reports about the immunotoxic potential of metals and metalloids, but in general, immunomodulatory action exerted by environmental chemicals is directly dependent on the exposure dose, route, and time. Higher concentrations exert immunosuppressive action. However, at lower concentration, immunostimulatory effects can be observed. The focus of this chapter will be on in vivo and in vitro immune responses to these environmental chemicals, but the potential mechanisms of biological effects exerted by these chemicals will also be discussed.
Authors:Simona Piccolella; Severina Pacifico Abstract: Publication date: 2015 Source:Advances in Molecular Toxicology, Volume 9 Author(s): Simona Piccolella, Severina Pacifico Cancer is a devastating disease affecting millions of people worldwide. Scientific research validly counteracts the onset of cancer and its resistances with a multiplicity of treatments. Healthy lifestyles and avoidance of exposure to potential carcinogens are highly recommended cancer preventive measures. Antioxidant and anti-inflammatory plant-derived polyphenols, peculiarly rich in plant dietary products, are thoroughly investigated as capable of hindering carcinogenesis in its various stages. Furthermore, a growing toxicological research, mostly based on cell and animal models, is identifying polyphenols or their formulations, properly obtained from plant sources, as promising anticancer agents with chemotherapeutic and chemopreventive effectiveness. Thus, polyphenols could also be employed as protectant agents, useful in overcoming the failures of the most common anticancer treatments. This chapter provides an update of the current scientific knowledge of plant polyphenols and all their anticancer-linked properties that make them a resource in toxicology worth exploring.
Authors:Guadalupe Eva; Ramon Pere Garriga Abstract: Publication date: 2015 Source:Advances in Molecular Toxicology, Volume 9 Author(s): María Guadalupe Herrera-Hernández, Eva Ramon, Pere Garriga In recent years, important advances have been made to decipher the multiple defense mechanisms of the retina (a highly specialized sense tissue) against several extreme conditions, such as constant exposure to systemic toxins, oxidative stress, and focused light rays. These studies have importantly contributed to improving our understanding of the principles underlying various drug- and light-induced disease processes, specifically at the eye level. When the different retinal cell layer defenses are overwhelmed by various xenobiotics, environmental agents such as pollution, cigarette smoke, or excessive light exposure, particularly high-frequency blue light and ultraviolet light, a pathological process may develop. Herein, we describe the main aspects of the structure and function of the retina in connection to some of the most relevant mechanisms which may generate retinal toxicity, and possible alternatives to counteract these effects. Furthermore, we summarize current knowledge about light-induced retinal toxicity as well as the effects of different natural and synthetic compounds on the molecular mechanisms underlying toxicity in the retina. Finally, the potential approaches undertaken to counteract these toxic effects, i.e., polyphenols and others, are discussed.
Authors:Francisco Bosca Abstract: Publication date: 2015 Source:Advances in Molecular Toxicology, Volume 9 Author(s): Francisco Bosca Molecular mechanisms of photosensitization induced by the antibacterial drugs fluoroquinolones (FQs) on biological systems are summarized. The photoreactivity of FQs is reviewed with special emphasis on the fundamental photophysical and photochemical properties of their excited states as well as their main photodegradation pathways. The photochemical mechanisms are analyzed on the basis of product studies, fluorescence measurements, and detection of short-lived intermediates by means of laser flash photolysis. After addressing the intrinsic processes, attention is focused on the photosensitized reactions between FQs and proteins or nucleic acids as the key biomolecules involved in the described photobiological adverse side effects. The varying behavior of FQs bound to DNA or albumin compared with the behavior of the drugs in bulk aqueous conditions explains the formation of the reported lesions caused by each FQ.
Authors:Luis M. Botana; Amparo Alfonso; Carmen Vale; Natalia Vilariño; Juan Rubiolo; Eva Alonso; Eva Cagide Pages: 1 - 33 Abstract: Publication date: 2014 Source:Advances in Molecular Toxicology, Volume 8 Author(s): Luis M. Botana , Amparo Alfonso , Carmen Vale , Natalia Vilariño , Juan Rubiolo , Eva Alonso , Eva Cagide Azaspiracids and yessotoxins (YTX) are marine toxins that still pose a scientific problem with regard to their mechanism of action. Azaspiracids are toxins that were linked to anionic channels, hERK potassium channels, c-Jun-N-terminal protein kinase kinases, adhesion proteins, and calcium pools. Their mechanism of action, although unknown, causes apoptosis. YTX are less well understood, the primary unclear aspect being whether or not they are in fact toxins, since there are no reports of a human intoxication. Possible targets of YTX have been proposed to be adhesion proteins, phosphodiesterases, PKC, the AKAP complex, or calcium pools. It is unclear if this toxin causes apoptosis, autophagia, or both, depending on the cell type. Also, the mechanism of action has been proposed as a basis for several possible therapeutic uses, as anticancer or anti-Alzheimer’s drug.
Authors:Lubinda Mbundi; Hector Gallar-Ayala; Mohammad Rizwan Khan; Jonathan L. Barber; Sara Losada; Rosa Busquets Pages: 35 - 105 Abstract: Publication date: 2014 Source:Advances in Molecular Toxicology, Volume 8 Author(s): Lubinda Mbundi , Hector Gallar-Ayala , Mohammad Rizwan Khan , Jonathan L. Barber , Sara Losada , Rosa Busquets Nanoparticles, bisphenols, mycotoxins, and brominated flame retardants are highly relevant species toxicologically that can contaminate food and drink through intentional administration or unintentionally from their migration from diverse sources such as packaging materials, cooking utensils, environmental contamination, and fungal activity. Although seemingly different, these contaminants share the common feature of being difficult to isolate and analyze in food. This chapter highlights the different challenges associated with the determination of the study toxins in food and drink and discusses current methods of analysis as well as methods and strategies to overcome the analytical challenges.
Authors:Ahmed Nabile Emam; Emad Girgis; Wagdy K.B. Khalil; Mona Bakr Mohamed Pages: 173 - 202 Abstract: Publication date: 2014 Source:Advances in Molecular Toxicology, Volume 8 Author(s): Ahmed Nabile Emam , Emad Girgis , Wagdy K.B. Khalil , Mona Bakr Mohamed Nanomaterials are defined as particles, fibers and tubes, composite materials, and nanostructured surfaces with at least one dimension smaller than 100nm (i.e., 10−9 m). Over the last decades, interest for engineered nanomaterials with specific physicochemical properties has grown dramatically. This opens great opportunities for use and is attractive in large number of applications that are being developed as well as by the increasing number of already marketed products. Therefore, due to their novel properties, a progressive concern about the potential effects of nanomaterials on human health has increased among toxicologists. Consequently, a great effort is underway to investigate the possible adverse effects of engineered nanomaterials, including genotoxicity. Plasmonic nanomaterials such as gold and silver and their composites have many biomedical applications, especially as drug delivery, cancer therapy, and diagnosis agents. This chapter summarizes the toxicological studies of gold nanoparticles and their dependence on size, shape, and capping materials. More light will be focused on our recent study on the genotoxicity investigations on nanomaterials especially gold and their alloys such as magneto-plasmonic nanoalloys (i.e., Au–Co alloy). In general, the toxicity of nanocomposite materials depends not only on the properties of their individual components but also on their morphology, dispersion, and interfacial characteristics.
Authors:Chiara Martina; Cirlini Claudia Falavigna Abstract: Publication date: 2014 Source:Advances in Molecular Toxicology, Volume 8 Author(s): Chiara Dall’Asta , Martina Cirlini , Claudia Falavigna Alternaria toxins are mycotoxins produced by Alternaria species. These fungi cause serious diseases in many crops such as cereals, oil seeds, and fruits. More than 70 Alternaria toxins have been reported and only some of them have been physicochemically characterized. Among the most common in food commodities, alternariol (AOH), alternariol methyl ether (AME), altenuene (ALT), and tenuazonic acid were mainly studied. Available in vitro data indicate that AOH, AME, and ALT are hydroxylated, mostly to catechol metabolites, and form glucuronide and sulfate conjugates. AOH and AME are genotoxic in bacteria and mammalian cells in vitro. Although there are no in vivo genotoxicity or carcinogenicity data available for Alternaria toxins, some indications of precancerous changes have been reported in esophageal mucosa of mice. In this review, the state of the art about the toxic effects of the major Alternaria toxins will be reported, and new data about their stability under in vitro human simulated gastrointestinal conditions will be described.
Authors:Melanie Esselen; Stephan Barth Abstract: Publication date: 2014 Source:Advances in Molecular Toxicology, Volume 8 Author(s): Melanie Esselen , Stephan W. Barth Topoisomerases manage the topological orientation of DNA by relaxing torsion stress in supercoiled DNA sectors and are thus essential for cell viability but might also have the capability to damage the genome finally leading to cell death in healthy and also cancerous cells. For targeting cancer cells, many drug-based as well as food-borne agents have meanwhile been discovered which exert their cellular effects through interactions with topoisomerases. This review introduces various food-borne flavonoid groups of isoflavones, catechins, flavones, flavonols, anthocyanins, and others which share bioactivity of “topoisomerase poisons” and/or “topoisomerase inhibitors.” Besides their direct targeting efficacy on topoisomerases, these food-based compounds also interact with chemotherapeutics which might implicate not only a benefit but also a risk in terms of their additional supply by diet or high-dosage supplements. Regarding a risk–benefit assessment, it has to be emphasized that the probability for reaching an effective (critical) dosage is lower for food than for highly concentrated food supplements.
Authors:Santos Silva; Olinda Pinto-Carnide Abstract: Publication date: 2014 Source:Advances in Molecular Toxicology, Volume 8 Author(s): Conceição Santos , Sónia Silva , Olinda Pinto-Carnide The increase of aluminum (Al) bioavailability in the soil seriously compromises plant growth and crop production. Al phytotoxicity highly depends on the interactions between Al and root cells, apoplast and symplast, which are influenced by genotype and environmental conditions (e.g., soil pH, nutrients availability). Within physiological parameters used to assess Al phytotoxicity, root elongation is widely known, either by cell wall extensibility and cell cycle impairment. Besides, recent data gave new insight on the relations between Al and nutrients, Al allocation in apoplast/symplast, cell oxidative stress homeostasis, cell differentiation, and photosynthesis. We also discuss some of the recent advances on plant tolerance including genetic mechanisms for Al exclusion, where organic acids play a crucial role, and mechanisms involved in Al compartmentation and tolerance. Important advances on the interaction of Al with genes regulating these physiological events are also highlighted.
Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Jason Matthews , Shaimaa Ahmed The aryl hydrocarbon receptor (AHR) and estrogen receptors (ERs) are ligand-activated transcription factors and members of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) and nuclear receptor (NR) superfamilies, respectively. The bHLH-PAS and NRs regulate many vital physiological processes including metabolism, circadian rhythm, differentiation, development, and reproduction. However, both receptor families are also associated with numerous human diseases. Reciprocal crosstalk between AHR and ERs is proposed to both positively and negatively impact human health. ERs are the most important targets in the treatment of breast cancer. The AHR, which is activated by many environmental pollutants, natural/dietary compounds, and endogenous substances, is a negative regulator of ER function. The role of ERα in AHR signaling is less clear as it is known to exhibit cell-type and promoter-specific differences. In this chapter, we will highlight the current understanding of AHR and ER crosstalk and toxicity.
Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Arno G. Siraki Aromatic amines (also known as arylamines) form a very important class of xenobiotics. The arylamine substructure is found in pesticides, carcinogens, and drugs. It is therefore unsurprising that arylamine drugs possess varying degrees of toxicity which ultimately depend on dose, exposure, and the particular genetic makeup of the individual. Arylamines have been shown to undergo oxidation reactions to produce reactive metabolites. This chapter will focus on a subset of reactive metabolites which are the arylamine-free radical metabolites. A detailed discussion on how these free radical metabolites form is presented, and association between the latter and toxicity reactions are discussed. Particular emphasis is devoted to the subject of arylamine-induced blood dyscrasias and recent advances as well as future prospects in this area.
Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Sushmita Sen , Jeffrey M. Field Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, so widespread that it is impossible for anyone to avoid exposure to them. They are the products of partial combustion, and exposure comes from the fossil fuels that we use to drive our cars, cook our food, warm our home, and fuel our industry. Other exposure comes from tobacco smoke and oil spills. PAHs are responsible for more cancers, primarily lung cancers, than any other carcinogen. The most studied PAHs are unsubstituted multi-ring structures. These compounds are not DNA reactive, and must be modified to become carcinogenic. Metabolic pathways modify PAH during the detoxification process. Three pathways have been extensively documented: the diol-epoxide pathway, the radical cation pathway, and the o-quinone pathway. Some PAHs are generated during combustion in oxygenated forms, usually as quinones. Quinones also form as PAHs are exposed to sunlight, for example, in an oil spill. These metabolic products damage DNA through distinct mechanisms: diol epoxides form bulky adducts with DNA, radical cations form depurinating adducts and quinones undergo futile redox cycling to generate reactive oxygen. Here, we discuss the evidence for these pathways in PAH carcinogenesis.
Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Umeo Takahama , Toshihiro Ansai , Sachiko Hirota Salivary nitrate derived from foods is reduced to nitrite and nitric oxide (NO•) by oral bacteria. NO• is transformed into NO2 •, N2O3, and ONOOH by chemical reactions, and nitrite is oxidized to NO2 • by salivary peroxidase. The formation of reactive nitrogen oxides becomes faster with the decrease in pH of dental plaque from 7 to 5. Reactive nitrogen oxides formed in acidified plaque can activate leukocytes through oxidation, nitration, and nitrosation of free and bacterial proteins in plaque and the gingival crevice. O2 •− and NO• produced by activated leukocytes can contribute to stresses to the gingival tissues. This chapter deals with mechanisms of production of reactive nitrogen oxides in the oral cavity, especially, acidified plaque. Since salivary nitrite is transported to the stomach, this chapter also deals with reactions of salivary nitrite in the stomach.
Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Oksana Lockridge The acute toxicity of organophosphorus (OP) nerve agents and pesticides is due to inhibition of acetylcholinesterase (AChE) activity in cholinergic nerve synapses. Delayed neuropathy involves OP binding to neuropathy target esterase (NTE) in neurons. AChE and NTE are serine hydrolases. In vitro studies have demonstrated that OP toxicants bind not only to serine hydrolases but also to proteins that have no active site serine, for example, Tyr 411 of human albumin and Lys 296 of mouse transferrin. Mice treated with low doses of chlorpyrifos have OP-modified tubulin in brain. Mass spectrometry has identified OP-modified albumin in the blood of humans self-poisoned by chlorpyrifos and dichlorvos. Albumin is weakly reactive with OP, but the presence of OP-modified albumin in humans suggests the existence of additional noncholinesterase OP targets. In conclusion, long-term adverse effects from OP exposure may involve OP modification of proteins that have no active site serine.
Abstract: Publication date: 2013 Source:Advances in Molecular Toxicology, Volume 7 Author(s): Sigeng Chen , John R. Cashman Organophosphate (OP) exposure continues to be a threat to both civilian and military personnel. Sensitive and specific methods for the detection and remediation are needed not only for public health but also for farmers who are exposed to OPs frequently. Although detection approaches based on a mass spectrometry are sensitive and reliable, they require expensive equipment and expert operators. In addition, instrumentation such as mass spectrometer cannot be easily deployed in the field. Attempts to make point-of-care approaches have been the trend in both detecting and rescuing OP exposure in the current research of OP toxicity. This chapter will discuss some recent progress reported concerning the immunodetection of OP exposure and improved antidote therapy in the remediation of OP exposure.
The indisputable benefits of combined antiretroviral therapies (cARTs) have lead to a dramatic change in the prognosis of human immunodeficiency virus (HIV) infection; a life-threatening disease a few decades ago is now perceived as a chronic illness in developed countries. However, as the eradication of HIV seems unlikely in the near future, chronic treatment with cART is unavoidable and increased concerns regarding the long-term adverse effects of these therapies are emerging. According to the World Health Organization, the most globally prescribed initial cART includes a non-nucleoside reverse transcriptase inhibitor (NNRTI). The currently approved NNRTIs are a class of chemically distinct compounds that share the possibility of undergoing biotransformation into electrophilic metabolites capable of reacting with biomacromolecules to afford covalent DNA and protein adducts that could be at the genesis of toxicity. Insights into the bioactivation mechanisms of the NNRTIs nevirapine, efavirenz, etravirine, and rilpivirine are presented in this review.
In South America, the incorporation of genetically modified organisms (GMO) engineered to be resistant to pesticides changed the agricultural model into one dependent on the massive use of agrochemicals. Different pesticides are used in response to the demands of the global consuming market to control weeds, herbivorous arthropods, and crop diseases. Here, we review their effects on humans and animal models, in terms of genotoxicity, teratogenicity, and cell damage. We also stress the importance of biomarkers for medical surveillance of populations at risk and propose the use of biosensors as sensitive resources to detect undesirable effects of new molecules and environmental pollutants. The compatibility of glyphosate, the most intensively used herbicide associated to GMO crops, with an integrated pest management for soybean crops, is also discussed.
Alcohol is recognized as a classic teratogen capable of inducing a wide range of developmental abnormalities. Alcohol abuse during pregnancy produces permanent brain damage in the fetus and is associated with the development of a life-long behavioral, social, and cognitive disorder now known as fetal alcohol spectrum disorder (FASD). The most clinically recognizable form of FASD is fetal alcohol syndrome (FAS) which is characterized by a set of characteristics including facial dysmorphogenesis, mental dysfunction, growth retardation, and cardiovascular and limb defects. Due to ethical constraints, human studies of FASD are very limited; however, our current understanding of FASD is mainly based on studies on several model vertebrate and invertebrate organisms. The fish embryo, especially zebrafish (Danio rerio) and Japanese medaka (Oryzias latipes), have proven utility for studying ethanol's damaging effects during morphogenesis. These two fish are long-established models for research in developmental biology and have been used to explore ethanol's effect on neurogenesis, cardiogenesis, intracellular signaling, neurobehavioral aspects, and apoptosis. Zebrafish are the center of attraction as a fish model of FASD; however, we have demonstrated that medaka embryos exposed to ethanol during development have several phenotypic features in craniofacial, cardiovascular structures and many biochemical parameters which are comparable to FASD phenotypes observed in human. In this chapter, we reviewed our findings and propose that medaka embryogenesis, like zebrafish, may be a very useful model for investigating the molecular endpoints of FASD.
Epigenetic modifications (e.g., DNA methylation, histone post-translational modifications, and microRNAs) play a vital role in embryonic development, tissue differentiation, and disease development through control of gene expression. There is increasing evidence that such alterations can greatly impact human health and may be particularly relevant for environmental toxicant-associated diseases. In this chapter, we discuss several high-priority toxicants and their relationship to epigenetic modifications. For each of these toxicants, epigenetic alterations are believed to play an important role in their associated detrimental effects. Specifically, we focus on representative toxicants from three different chemical classes: carcinogenic metals, endocrine disruptors, and polycyclic aromatic hydrocarbons. We detail the current understanding of epigenetic alterations associated with exposure to each of these toxicants as well as how these alterations may contribute to deleterious health effects.
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