Xenobiotic exposure

Phenols also constitute a major source of xenobiotic exposure to the body in the form of drugs and environmental pollutants. Oxidative metabolism of these compounds can lead to physiological damage, therefore the metabolism of these compounds is of great interest. LCEC has been a powerful tool for investigating the metabolism of aromatic compounds by the cytochrome P-450 system LCEC... 

The majority of early publications that can be reasonably identified as comprising immunotoxicology reported altered resistance to infection in animals exposed to various environmental or industrial chemicals. Authors logically concluded that xenobiotic exposure suppressed immune function since the immune system is ultimately responsible for this resistance to infection. Subsequent studies demonstrated that suppression of various cellular and functional endpoints accompanied or preceded increased sensitivity to infection, and that administration of known immunosuppressants likewise decreased host resistance. The human health implications of these studies, that chemical exposure reduced resistance to infection, drove the initial focus of many immunotoxicologists on functional suppression, and provided the theoretical and practical underpinnings of immunotoxicity testing. 

Induction of P-450 Metabolism and Isoenzymes. When organisms are exposed to certain xenobiotics their ability to metabolize a variety of chemicals is increased. This phenomenon can produce either a transitory reduction in the toxicity of a drug or an increase (if the metabolite is the more toxic species). However, this may not be the case with compounds that require metabolic activation. The exact toxicological outcome of such increased metabolism is dependent on the specific xenobiotic and its specific metabolic pathway. Since the outcome of a xenobiotic exposure can depend on the balance between those reactions that represent detoxication and those... 

The major advantage of an in vitro system is that it represents a simplified system which allows the experimenter to address questions which cannot be tested in vivo. These systems can allow analysis of activation or metabolism at the single enzyme level. They can test proposed pathways of metabolism or activation. Such studies are not practical with in vivo systems. The major disadvantage is that in vitro systems are a simplified system and the results can be easily over-interpreted. In vitro systems cannot model the pharmacokinetics or toxicokinetics of xenobiotic exposure in vivo. In addition, there may be other, unappreciated enzymes or factors which influence metabolism/toxicity in vivo which are not present in the in vitro system. 

Finally there is growing concern that the developing immune system may be particularly vulnerable to xenobiotic exposures and that perinatal and/or in utero exposures may have a lifelong impact on susceptibility to infectious, allergic, or autoimmune disease. As in other areas of toxicology, tests designed to assess the risk of immuno-toxicity for adults may not be sufficient to protect children and research is currently underway to determine how best to meet this need. 

Clearly, exposure to xenobiotics can have a number of effects on the immune system that in turn can affect an array of health outcomes. In some areas of immunotoxicology significant progress has been made in terms of identifying and understanding the risks associated with xenobiotic exposure. In other areas more research is needed. 

The two major kinds of samples analyzed for xenobiotics exposure are blood and urine. Both of these sample types are analyzed for systemic xenobiotics, which are those that are transported in the body and metabolized in various tissues. Xenobiotic substances, their metabolites, and then-adducts are absorbed into the body and transported through it in the bloodstream. Therefore, blood is of unique importance as a sample for biological monitoring. Blood is not a simple sample to process, and subjects often object to the process of taking it. Upon collection, blood may be treated with an anticoagulant, usually a salt of ethylenediaminetetraacetic acid (EDTA), and processed for analysis as whole blood. It may also be allowed to clot and be centrifuged to remove solids the liquid remaining is blood serum. 

Elucidate and characterize the mechanisms responsible for tissue-specific differential gene expression in rat in liver and hepatoma cells so as to understand the molecular basis of gene expression under normal and pathophysiological (i.e., following both xenobiotic exposure [to 2,3,7,8-TCDD or 3-methylcholantherene] and during hepatocarcinogenesis) conditions... 

Smoking, drugs, industrial chemicals and foods, represent the major sources of exposure to xenobiotics for modern man. Because diet furnishes the most variable and continuous array of xenobiotic exposure, the emphasis of this symposium is the... 

Curcumin is reported to prevent DNA damage, even in individuals who may be genetically susceptible to the toxic effects of xenobiotic exposures, and is also able to exert antimutagenic/anticarcinogenic properties at levels as low as 0.1-0.5% in the diet (Polasa et al., 2004). 

Figure 13.13. ARE activation by Nrf2. Nrf2 associates with Keapl, a repressor protein of Nrf2, in the cytoplasm. Upon xenobiotic exposure to cells, upstream kinase pathways are activated and induce dissociation of Nrf2 from Keapl. The hberated Nrf2 translocates into nucleus and dimerize with a small Maf protein and bind to an ARE enhancer sequence identified in various phase II genes.

For the purposes of this chapter, reproductive toxicity will refer to any manifestations of xenobiotic exposure, including endocrine disruption (see discussion below), reflecting adverse effects on any of the physiological processes and associated behaviors and/or anatomical structures involved in animal reproduction or development (Figure 36.1). This is a fairly broad definition which encompasses developmental toxicity, as well as any toxic... 

A biomarker of susceptibility can be defined as "an indicator of an inherent or acquired limitation of an organism to respond to the challenge of exposure to a specific xenobiotic substance" [4]. These markers indicate differences in individuals or populations that affect the body s response to xenobiotic exposure. They may include variations in the balance between enzymes that detoxify or enhance the toxicity of chemicals, genetic differences in the capacity of cells to recover from injury, inherited genetic defects that increase the risk of cancer. 

Oxidative stress (OS) has been advanced to explain many of the hazardous effects of xenobiotic exposure including carcinogenesis. OS theory as it applies to particular xenobiotic impacts is addressed in succeeding chapters, which address the different target organs of foreign chemicals. The discussion here is an introductory one. The reader is referred to two articles in the literature and the references contained therein for a more comprehensive discussion. I5,6 ... 

Exposures to xenobiotics affect OS adversely by increasing the body s ROS and thereby upsetting the balance between the natural production and elimination of free radicals. OS has been implicated in numerous deleterious conditions brought about by xenobiotic exposures in humans. These conditions include infertility, central and peripheral nervous system effects, respiratory effects, liver and kidney function, cardiovascular effects, and cancer. Each of these is addressed in the ensuing chapters. 

It is universally accepted that ionizing and UV electromagnetic radiation induce toxic effects in man. It has been shown above that these toxic effects are exacerbated when irradiation is coupled with xenobiotic exposure. Conversely, the toxic effects of xenobiotic exposure are enhanced by simultaneous exposure to ionizing or UV radiation. 

Xenobiotic exposures can impact female fertility in humans in several ways. Much of the published research on xenobiotic impact on female infertility has concerned itself with the effects of pesticides. The effects, however, are just as applicable to other toxicants. Interference with any of the following six processes adversely impacts fertility ... 

Male fertility depends upon normal development during the fetal period extending through childhood growth and puberty. Xenobiotic exposures after puberty can also affect fertility. 

Xenobiotic exposure can adversely affect bones, joints, connective tissue, and muscles. Rheumatoid arthritis, osteoporosis, osteomalacia, systemic sclerosis, scleroderma, systemic lupus erythematosus, and spina bifida are musculoskeletal diseases that have been associated with toxic chemical exposures. Most of these associations, however, have been made to single chemical exposures and not to mixtures. This chapter cites the evidence on which those associations are based and discusses the available examples of mixtures that have been implicated. 

Decreased immunological competency can lead to susceptibility to infections, and it can also lead to cells that lack the capacity to control their growth. In contrast, excess activity can cause the immune system to attack the host organism, itself. Both of these adverse effects can result from xenobiotic exposure. 

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