Veterans and Agent Orange Update 11 (2018) (2018) / Chapter Skim
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4 Biologic Mechanisms
4 Biologic Mechanisms
Pages 69-114
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From page 69... ...
Additionally, information about three emerging subjects in molecular and biologic science -- epigenetics, developmental immunotoxicology, and oxidative stress -- are discussed because they provide insights into the potential mechanisms that could explain biologic responses associated with exposure to the herbicides sprayed in Vietnam. The establishment of biologic plausibility through laboratory studies strengthens the case for a cause–effect relationship between herbicide exposure and health effects that has been reported in epidemiologic studies.
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From page 70... ...
. Animal studies may involve additional routes of exposure that are not ordinarily encountered by humans, such as intravenous or intraperitoneal injection, when a chemical is injected into, respectively, the bloodstream or the abdominal cavity.
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From page 71... ...
This is different from elimination, which refers to the disappearance of the parent molecule from the bloodstream. The rate of excretion of a chemical from the body is often limited by the rate of metabolism of the parent chemical into more water-soluble, readily excreted metabolites.
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From page 72... ...
Animal and cell culture studies are often conducted at higher exposures and for shorter durations than are typical in human exposures, which can influence biotransformation. For that reason, attempts to extrapolate from experimental animal studies to human exposures must be done extremely carefully.
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From page 73... ...
Chronic Systemic Toxicity There is some evidence from chronic experimental animal studies that ingesting high doses of picloram affects the liver. Several studies have reported various effects of technical-grade picloram on the livers of rats.
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From page 74... ...
. No other toxic effects of chronic exposure to picloram have been reported.
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From page 75... ...
Potential cacodylic acid exposure of Vietnam veterans would have involved direct exposure to exogenous DMAV, rather than exposure to inorganic arsenic, which would have led to the endogenous formation of MMAV and MMAIII and then DMAV. The old hypothesis that methylation of inorganic arsenic was a detoxifying mechanism has been dispelled by newer studies.
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From page 76... ...
of exposure was inorganic arsenic and have only considered and reviewed toxicologic studies in which the animals were directly exposed to DMA. Information about effects of inorganic arsenic exposure may be found in reviews by the International Agency for Research on Cancer (IARC, 2012a)
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From page 77... ...
, but these models have limited relevance for assessing potential harm to Vietnam veterans, who are presumed to have been directly exposed to DMAV. Although epidemiologic studies of direct exposure to DMAV are not available, investigations into the relationship between health outcomes and the metabolic profiles of humans exposed to inorganic arsenic provide some insight into the roles of the individual metabolites in producing adverse outcomes.
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From page 78... ...
Genotoxicity and Carcinogenicity DMAIII and DMAV are genotoxic and increase oxidative stress and cause DNA damage, particularly aneuploidy, but they are poor mutagens (Rossman and Klein, 2011)
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From page 79... ...
Gene-expression profiling of bladder urothelium after chronic exposure to DMAV in drinking water showed significant increases in genes that regulate oxidative stress (Sen et al., 2005)
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From page 80... ...
Studies have also found that an oral exposure of adult mice to 200 ppm DMAV in addition to fetal inorganic arsenic exposure can act as a promoter of renal and hepatocellular carcinoma, markedly increasing tumor incidence beyond that produced by the fetal arsenic exposure alone (Tokar et al., 2012)
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From page 81... ...
It is believed to exert a direct toxic effect by generating oxidative stress, inducing epigenetic dysregulation, binding to thiols, and interfering with DNA repair mechanisms. These mechanisms of action may be involved in gene damage and carcinogenesis.
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From page 82... ...
Data on both compounds are consistent among species and support the conclusion that the absorption of oral or inhaled doses is rapid and complete. One study indicates that 2,4-D can bind to innate intestinal, intracellular lipid-binding proteins, which may be how these compounds move through columnar absorptive epithelial cells from the intestines to systemic distribution (Carbone and Velkov, 2013)
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From page 83... ...
2,4-D is also an irritant of the gastrointestinal tract that causes nausea, vomiting, and diarrhea. Chronic exposure to 2,4-D at relatively high concentrations has been shown to produce a variety of toxic effects, including hepatic and renal toxicity, neurotoxicity, and hematologic changes.
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From page 84... ...
Morphological and skeletal defects and low birth weight were observed in the fetuses of dams treated with only 2,4-D, but not in those whose mothers were also treated with vitamin E, thereby suggesting that 2,4-D exposure elicits fetotoxicity through inducing oxidative stress. In vitro exposure of human erythrocytes to 2,4-D caused changes in antioxidant enzyme activity as well as increased protein carbonyls, indicating induction of oxidative stress (Bukowska, 2003)
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From page 85... ...
Thus, relative telomere length might show an effect with c umulative 2,4-D exposure in blood leukocytes, but the mechanisms of action and consequences for disease are unknown.
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From page 86... ...
In laboratory animals, oral administration of TCDD has been shown to result in absorption of 50–93% of the administered dose (Nolan et al., 1979; Rose et al., 1976)
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From page 87... ...
Animal studies have demonstrated that the presence of soil or lipophilic agents dramatically reduces dermal absorption of TCDD: application in an activated carbon–water paste essentially eliminates absorption in contrast with the absorption of the pure compound dissolved in solvents. The oral bioavailability of TCDD and related compounds also depends on the matrix: contaminated breast milk and food products have much higher bioavailability than soil-bound or sediment-bound TCDD, and activated carbon essentially blocks oral bioavailability (Olson, 2012)
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From page 88... ...
in very high TCDD exposures. Two metabolites of TCDD (2,3,7-trichloro-8-hydroxydibenzop-dioxin and 1,3,7,8-tetrachloro-2-hydroxydibenzo-p-dioxin)
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From page 89... ...
The lethal toxicity of TCDD varies widely among animal species; the oral LD50 of the chemical varies from 1 μg/kg in guinea pigs to 5,000 μg/kg in hamsters. The developing fetus, however, is especially vulnerable to TCDD exposure, and there is only about a 10-fold variability in fetal lethal potency among these species (Kransler et al., 2007; Peterson et al., 1993; Poland and Knutson, 1982)
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From page 90... ...
In laboratory animals, exposure to TCDD commonly results in an increase in CYP1A1 in most tissues; CYP1A1 therefore is often used as a marker of TCDD exposure. Related enzymes whose levels are also increased with TCDD exposure include CYP1B1 and CYP1A2, which together with CYP1A1 are capable of biotransforming some procarcinogens to potentially mutagenic and carcinogenic metabolites.
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From page 91... ...
In the adult, proper differentiation is required for the normal functioning of the body -- for example, in maintaining a normally responsive immune system. The processes of controlled cell death, such as apoptosis, are similarly important during the development of the fetus and are necessary for normal physiologic functions in the adult.
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From page 92... ...
The ability of TCDD to bind to AHR with high affinity is necessary -- but not sufficient -- to produce most of the adverse effects associated with TCDD exposure, including those from direct TCDD binding to and activation of the AHR and later alterations in the expression of TCDD-regulated genes as well as changes to those signaling pathways altered through interactions with the canonical AHR pathway (Poland and Knutson, 1982; Safe, 1990; Schmidt and Bradfield, 1996; Whitlock, 1990)
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From page 93... ...
. In the non-canonical pathway, activation of the AHR through binding TCDD, or other ligands, results in cytoplasmic interactions leading to rapid changes in intracellular calcium, activation of signaling pathways, and direct binding to other transcription factors.
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From page 94... ...
takes place within 15 minutes of TCDD exposure (Dong and Matsumura, 2008; S
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From page 95... ...
. Because of the presence of the AHRE motif in their gene promoters, other metabolizing genes were tested and found to be induced by AHR ligands, which led to the identification of a so-called AHR gene battery of phase I and phase II detoxification genes that code for the drug-metabolizing enzymes CYP1A1, CYP1A2, CYP1B1, NQO1, ALHD3A1, UGT1A2, and GSTA1 (Nebert et al., 2000)
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From page 96... ...
Ahr knockout rats also demonstrate resistance to the toxic effects of TCDD and, in contrast to mice, display pathological alterations to the urinary tract in the absence of TCDD (Harrill et al., 2013)
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From page 97... ...
consensus toxicity factor and TEQ values were in the effects of PCBs, which were inactive in the human cell line assays. The computational tools used by Larsson et al.
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From page 98... ...
Interim TEF values have been established for brominated congeners by the 2011 joint WHO–UN Environment Programme meeting to evaluate the WHO TEF scheme. The recommendation is to use the TEF of the corresponding chlorinated congener as an interim TEF value for brominated congeners for human risk assessment (van den Berg et al., 2013)
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From page 99... ...
Although TCDD is carcinogenic in humans and laboratory animals, it is generally classified as nongenotoxic and nonmutagenic (Wassom et al., 1977)
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From page 100... ...
Both individual values and TEQs were estimated. Multivariate linear regression was used to study associations between natural log-transformed leukocyte telomere length and persistent organic pollutant quartiles.
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From page 101... ...
In vitro studies in cell lines have identified altered DNA methylation and expression in genes related to adipocyte differentiation following TCDD exposure (van den Dungen et al., 2017) and in CYP1A1 following PCB 126 exposure (Vorrink et al., 2014)
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From page 102... ...
Earlier VAO Update reports address the other toxic effects of TCDD in greater detail, including the relationship between human and animal-model sensitivity to exposure. Summary of Biologic Plausibility That TCDD Induces Adverse Effects in Humans Mechanistic studies in vitro and in laboratory animals have characterized the biochemical pathways and types of biologic events that contribute to the adverse effects of exposure to TCDD.
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From page 103... ...
For example, the concentrations of TCDD used in animal studies can be many times higher than was typical in the TCDD exposures of Vietnam veterans during their military service. In addition, TCDD is a persistent organic pollutant, and this results in uman h exposure that occurs over a lifetime, whereas animal studies seldom exam ine chronic low-level exposures that occur over a period of many months or years, except those that evaluate chronic toxicity or carcinogenicity.
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From page 104... ...
In addition to the COIs, the environmental factors that commonly influence human responses include diet, prescription and over-the-counter pharmaceu ticals, cigarette smoking, alcohol consumption, physical activity, the micro biome, and stress. Stress (not to be confused with oxidative stress)
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From page 105... ...
. It was not until the 1970s, however, that the first molecular epigenetic factor was described: DNA methylation, the chemical addition of a methyl group to DNA (Holliday and Pugh, 1975)
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From page 106... ...
The latter transcriptional regulation is referred to as "epigenetic silencing," and is mediated either by covalent modifications of chromatin (such as H3 methylation at Lys9) or by DNA methylation (Verdel and Moazed, 2005)
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From page 107... ...
Researchers rely on more accessible proxy tissues such as blood leukocytes, saliva, buccal cells, or placenta. A second consideration is that DNA methylation levels change as a function of age in both humans and animal models and that these age-related changes in methylation are gene- and tissue-specific, can be either random or predictable, and are thought to play a role in chronic disease development.
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From page 108... ...
There is precedent within the endocrine disrupting chemical literature for epigenetic alterations to have low-dose and non-monotonic effects, which are not necessarily linked to blocking or mimicking hormones, but may occur through other mechanisms such as oxidative stress or direct interactions with any of the many epigenetic enzymes and co-factors necessary for epigenetic gene regulation (Tapia-Orozco et al., 2017)
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From page 109... ...
In summary, the ability of epigenetic mechanisms to regulate gene expression coupled with the interaction of the epigenome and the environment, including multi- and trans-generational effects, might underlie the ability of xenobiotic exposure to contribute to disease development and the potential for offspring to inherit the effects of the disrupted epigenetic processes. Developmental Immunotoxicity A second emerging field in the biologic sciences that may provide insight into the mechanism of xenobiotic-induced disease is developmental immunotoxicity, the study of the disruption of the developing immune system by xenobiotic exposure.
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From page 110... ...
People who have particular genotypes may be at increased risk for specific chemicalinduced developmental immunotoxicity on the basis of heritable factors that affect etabolism or immune vulnerability. m The heightened sensitivity of the developing immune system is due to the existence of critical developmental windows of vulnerability during which environmental interference with key steps of immune maturation can change the entire course of immune development and result in later-life immune dysfunction and an increased risk of disease.
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From page 111... ...
For example, both oxidative stress and toxicant exposures have been associated with metabolic syndrome, insulin resistance, diabetes, obesity, and cardiovascular complications (Bonomini et al., 2015; Lang et al., 2008)
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From page 112... ...
Measurements included PCBs, organochlorine pesticides, octachlorinated dibenzo-p-dioxin, and polybrominated diphenyl ethers, and TEQ values were calculated for dioxin and dioxin-like mono-ortho PCBs via the van den Berg method. Oxidative stress markers consisted of protein stress markers (e.g., homocysteine, GSH, GSSG)
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From page 113... ...
(2017) demonstrated that TCDD exposure increased the levels of the pro-inflammatory cytokines IL-1β and IL-6, which could induce blood–brain barrier breakdown and contribute to the pathogenesis of a variety of neurologic disorders.
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