Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 32
Veterans and Agent Orange: Update 1998 3 Toxicology As in Veterans and Agent Orange (VAO) and Veterans and Agent Orange: Update 1996 (Update 1996), this review summarizes the experimental data that serves as a scientific basis for assessment of the biologic plausibility of health outcomes reported in epidemiologic studies. Efforts to establish the biologic plausibility of effects due to herbicide exposure in the laboratory strengthen the evidence for the herbicide effects suspected to occur in humans. Differences in chemical levels, frequency of administration, single or combined exposures, preexisting health status, genetic factors, and routes of exposure significantly influence toxicity outcomes. Thus, any attempt to extrapolate from experimental studies to human exposure must carefully consider such variables before conclusions are made. Multiple chemicals were used for various purposes in Vietnam. Four herbicides documented in military records were of particular concern and are addressed here: 2,4-dichlorophenoxyacetic acid (2,4-D); 2,4,5-trichlorophenoxyacetic acid (2,4,5-T); picloram; and cacodylic acid. In addition, the toxicologic properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), a contaminant of 2,4,5-T, are discussed. This chapter focuses to a large extent on the toxicological effects of TCDD, because considerably more information is available on TCDD than on the herbicides. SUMMARY Toxicokinetics New information on the distribution of 2,4-D and the metabolism of cacodylic acid has improved understanding of how the body handles these sub-
OCR for page 33
Veterans and Agent Orange: Update 1998 stances. 2,4-D enters the brain, but only to a limited extent, and its uptake by the brain appears to be an energy-dependent process. Cacodylic acid is one of the major metabolic products of ingested arsenic in mammals. Studies using skin taken from mice report that the absorption of cacodylic acid is influenced by the substance in which it is dissolved and the length of time that cacodylic acid remains in contact with the skin. TCDD, unlike the herbicides, stays in the body for a long time. In humans about half is eliminated every 8.5 years. It is removed from the body as it is metabolized to less toxic forms that are more easily eliminated in the urine than TCDD itself. The length of time that TCDD remains in the body increases with increasing body fat. New evidence based on animal models suggests that rats and humans tend to handle TCDD in body tissues in similar ways. However, rats tend to excrete TCDD more quickly. Rats are most likely to absorb TCDD through food and air and this fact may carry over to humans. However, the types of TCDD and other dioxins that accumulate in the body may differ markedly between humans and rodents. Mechanisms of Toxic Action Little is known about the way in which the herbicides produce toxic effects in animals. Recent studies have focused on the mechanisms of cellular toxicity of 2,4,5-T. For example, some studies using animal tissues suggest that 2,4,5-T may alter nerve and muscle function by interacting with chemicals that participate in nervous system function. 2,4,5-T may induce mutations at different stages of cell development. Finally, it may alter the cellular process involved in the elimination of harmful carcinogens. To date, the consensus is that TCDD is not directly toxic to the body's genetic material. However, it may affect enzymes and hormone levels, which in turn may produce adverse effects. Recent studies confirm earlier findings that most of the toxic effects of TCDD are caused by its binding to a protein called the aryl hydrocarbon receptor (AhR). The binding of TCDD to this protein triggers various events that result in toxic sequelae. However, some tests suggest that other events, in addition to the binding of TCDD to the AhR, are involved. Studies of the AhR and its partner protein Arnt (aryl hydrocarbon nuclear translocator protein) indicate that similar proteins exist in different species and interact with a number of other proteins to produce an effect. Researchers have recently bred mice that lack the AhR protein. It is anticipated that these mice will allow more informative studies of the way TCDD reacts with the AhR to produce a toxic effect. Disease Outcomes Disease outcomes associated with herbicide exposures continue to be debated. Some cellular-level effects have been identified, although it is not clear
OCR for page 34
Veterans and Agent Orange: Update 1998 what impact these may have on living organisms. Other studies suggest disease effects including neurotoxicity and kidney, liver, and muscle damage at certain high dose levels in particular animal species; however, translating these results to the exposures experienced by veterans and others remains problematic. 2,4-D appears to affect the membrane sheath around nerve cells. Other studies support the view that 2,4-D may disrupt cellular processes in the liver, and reports of kidney and muscle damage have been published. Results from studies indicate that high doses of 2,4-D are necessary to produce these effects. A case-control study of dogs exposed to 2,4-D in addition to other pesticides used in yard work, reported an increase in lymphomas associated with exposure. The limited evidence published during the past two years suggest that cacodylic acid may promote cancer in rats. Several recent studies have examined the role of TCDD in producing certain disease outcomes in animals, including acute toxicity, dermal toxicity, liver toxicity, neurotoxicity, immunotoxicity, reproductive and developmental toxicity, and cancer. A prominent symptom of the acute toxicity of TCDD is the loss of fat tissue and body weight, a phenomenon known as wasting syndrome. Several mechanisms are under investigation including inhibition by TCDD of sugar transport activity, effects on fat cell differentiation, and effects on certain receptors and enzymes. There is some evidence to suggest that gender differences exist in the response of fat cells to TCDD. TCDD has also been shown to affect the development of skin cells by binding to the AhR. This effect is antagonized by retinoids. Liver enlargement has been shown to occur following high doses of TCDD. The mechanism by which TCDD affects the liver is still under investigation. Recently, it has been shown to inhibit DNA synthesis of liver cells, decrease certain receptors in liver cell membranes, and inhibit liver enzymes. Animal and test-tube studies continue to emphasize the importance of alterations in neurological systems as underlying mechanisms of TCDD-induced behavioral dysfunction. TCDD can affect the metabolism of serotonin, a substance in the brain that can modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In certain brain cells, there is evidence that TCDD may increase the uptake of calcium. It is known that TCDD exposure causes a broad range of immunologic effects in experimental animals. Recent studies support earlier data that TCDD decreases immunity and host resistance to pathogenic microorganisms. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be mediated primarily through the AhR, but some components of immunosuppression have been shown to act independently of this receptor.
OCR for page 35
Veterans and Agent Orange: Update 1998 Low doses of TCDD administered to experimental animals alter reproductive development and fertility of the offspring. When TCDD is administered to pregnant rats, malformations of the external genitalia are observed in female offspring. Functional reproductive alterations in female offspring are also observed after TCDD exposure, including decreased fertility rates and reduced fecundity. Studies in male rats and hamsters have shown that decreased daily sperm production is one of the most sensitive effects of exposure to TCDD in the womb and through breast milk. Results also suggest that TCDD exposures selectively impair rat prostate growth and development. TCDD has been shown to affect blood serum hormone levels. This outcome is thought to be due partially to the action of TCDD on the pituitary gland. Several reports published during the reference period focused on the mechanism by which TCDD induces cleft palates in experimental animals. Evidence suggests that this effect involves the AhR. There have also been reports of developmental defects in the cardiovascular system of TCDD-treated animals. Evidence suggests that cells lining the blood vessels are a primary target of TCDD-induced developmental cardiovascular toxicity. Studies continue to focus on the mechanism by which TCDD induces cancer in animals. Although there is considerable evidence that TCDD-induced cancer is mediated by the AhR, it does not appear to be solely responsible. There is also evidence that the mechanism by which TCDD induces tumor promotion may involve reactive molecules containing oxygen, which are known as oxygen radicals. It is hypothesized that a release of oxygen radicals by TCDD causes DNA damage that could lead to mutation and cancer. There is also evidence that TCDD tumor promotion may be due to its ability to interfere with intercellular communications. Inconsistencies reported in the molecular basis of dioxin' s actions reflect the degree of tissue, cell, and gene specificity that characterizes the toxic response. Relevance To Human Health Exposure to 2,3,7,8-TCDD, a contaminant in some of the herbicides used in Vietnam, has been associated with both cancer and noncancer end points in animals. Studies in animals indicate that TCDD effects are mediated through the AhR. Although structural differences in the AhR have been identified, it operates in a similar manner in animals and humans, and a connection between TCDD exposure and human health effects is, in general, considered biologically plausible. Evidence has also begun to accumulate for non-AhR mediated effects. Animal research indicates that TCDD can both cause cancers or tumors and enhance the incidence of certain cancers or tumors in the presence of known carcinogens. However, experimental animals greatly differ in their susceptibility to TCDD-induced effects, and the sites at which tumors are induced also varies
OCR for page 36
Veterans and Agent Orange: Update 1998 from species to species. Other noncancer health effects vary according to dose and to the animal exposed. Controversy exists over whether the effects of TCDD and other exposures are threshold dependent, that is, whether some exposure levels may be too low to induce any effect. Limited information is available on the biologic plausibility of herbicide health effects not connected with TCDD. Although concerns have been raised about non-dioxin contaminants of herbicides, far too little is known about the ubiquitousness and concentration of these compounds in the formulations used in Vietnam to draw conclusions about their impact. Considerable uncertainty remains about how to apply this information to evaluation of the potential health effects in Vietnam veterans of herbicide or dioxin exposure. Scientists disagree over the extent to which information derived from animal and cellular studies predicts human health outcomes and the extent to which health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Research on biological mechanisms is burgeoning, and subsequent VAO updates may have more and better information on which to base conclusions. VAO AND UPDATE 1996—OVERVIEW Chapter 4 of VAO and Chapter 3 of Update 1996 review the results of animal and test-tube studies published until 1995 that investigated the toxicokinetics, mechanism of action, and disease outcomes of TCDD and herbicides. According to these earlier reviews, TCDD elicits a diverse spectrum of biological sex-, strain-, age-, and species-specific effects, including carcinogenicity, immunotoxicity, reproductive and developmental toxicity, hepatotoxicity, neurotoxicity, chloracne, and loss of body weight. The scientific consensus is that TCDD is not genotoxic and that its ability to influence the carcinogenic process is mediated via epigenetic events such as enzyme induction, cell proliferation, apoptosis, and intracellular communication. The toxicity of the herbicides used in Vietnam has been poorly studied. In general, the herbicides 2,4-D, 2,4,5-T, cacodylic acid, and picloram have not been identified as particularly toxic substances since high concentrations are often required to modulate cellular and biochemical processes. A comprehensive description of the toxicological literature published until 1995 can be found in VAO and Update 1996. UPDATE OF THE SCIENTIFIC LITERATURE—OVERVIEW Toxicokinetics A limited number of studies have been published since Update 1996 that examine the biologic and toxic effects of 2,4-D. Toxicokinetic studies using rabbits suggest that uptake of 2,4-D by the brain is restricted by the developing,
OCR for page 37
Veterans and Agent Orange: Update 1998 as well as the mature, blood-brain barrier. In hamsters, cellular 2,4-D uptake appears to be an energy-dependent process. During the reference period since the publication of Update 1996, the disposition of TCDD in humans has been investigated in two studies. Based on multiple serum measurements collected over a 10-year period from 213 veterans of Operation Ranch Hand, the mean decay rate of TCDD was estimated to be 0.0812 per year, with a corresponding half-life estimate of 8.532 years. In these veterans, half-life increased significantly with increasing body fat, but not with age or relative changes in the percentage of body fat. In another human study, the impact of breastfeeding on the body burden of dioxin-like chemicals in Arctic Inuit people was investigated. Toxicokinetic modeling revealed that breast feeding strongly influences the body burden of TCDD during childhood but not after 20 years of age. In addition, liver and adipose tissue concentrations in adults greater than 20 years of age appeared to be lower than those associated with cancer and adverse reproductive effects in laboratory animals. Using a physiologically based model that describes the distribution kinetics of dioxin-like chemicals in various mammalian species, the kinetic profile of TCDD was found to be similar in rats and humans, although the half-lives differ considerably between species. The half-life of TCDD in rats and humans is measured in weeks and years, respectively. Comparative studies of the systemic absorption of TCDD in rats following oral and inhalation exposures indicate that both exposures are significant routes of absorption—an observation that is of relevance to humans given the similarities in kinetic profiles between rats and humans. In addition, for a given body burden, the adipose tissue concentrations have been found to vary in an inversely proportional manner to the mass of adipose tissues. Despite similarities in the toxicokinetic profile of rats and humans, some data suggest that humans may bioaccumulate higher levels of certain dioxins than mice due to interspecies metabolic differences. Results from another model of the disposition of TCDD in the rat indicate that TCDD increases the enzymatic activity of UDP-glucuronosyltransferase (UGT) and the levels of blood thyroid-stimulating hormone (TSH). Calculated increases in blood TSH levels are consistent with prolonged stimulation of the thyroid and may represent an early stage in the induction of thyroid tumors identified in previous two-year bioassays. This suggests that increases in UGT activity may be a useful biomarker for tumorigenic changes in hormone levels after TCDD exposure. However, certain noncancer end points may be more significant in assessing human health risks to TCDD than cancer end points. For instance, immune suppression and enzymatic induction have been found to occur at lower doses and under conditions more relevant to general population exposure conditions. In assessing the risk of humans to dioxins, it should also be noted that recent data suggest that toxic equivalency factors (TEFs) derived from short-term assays may not adequately predict the relative potencies of this class of compounds following chronic exposure.
OCR for page 38
Veterans and Agent Orange: Update 1998 Mechanisms of Toxic Action The mechanisms of cellular toxicity of 2,4,5-T have been the focus of a number of recent studies. One study presents compelling evidence that 2,4,5-T interacts with choline to generate false cholinergic messengers that alter neuronal and muscular function. Another study found that 2,4,5-T can induce mutations at different germ cell stages. Finally, there is some evidence that 2,4,5-T modulates cellular metabolism to alter the expression of membrane pumps and drug-metabolizing enzymes involved in the disposition of chemical carcinogens. Dimethylarsinic acid (cacodylic acid, DMA) is one of the major methylated metabolites of ingested arsenicals in mammals. During the reference period, toxicokinetic studies reported that the rates of in vitro dermal absorption of DMA can be influenced by both the vehicle of administration and the duration of exposure. Scientific reports published during the past two years continue to focus on the mechanism by which TCDD exerts its effects. Structural and functional studies of the AhR and Arnt indicate that both proteins are highly conserved, are found in diverse vertebrate groups, and interact with a large number of proteins to influence nuclear events. In vitro studies have confirmed in vivo findings regarding the functional binding domains of mouse AhR that interact with the heat shock protein (hsp90). Other results continue to support the view that TCDD influences patterns of gene expression by modulating transcriptional and post-transcriptional events. Such responses are often mediated by the AhR but exhibit considerable tissue and cell specificity. From a toxicologic perspective, the development of AhR knockout mice has been an important advance because it has helped establish a definitive association between the AhR and TCDD-mediated toxicities. Some studies suggest that specific patterns of Arnt expression differ in certain tissues from those of the AhR and that Arnt may have roles in normal embryonic development independent of the AhR. The recent discovery that the oxygen-regulated transcription factor HIF-1α and the AhR share a common heterodimerization partner Arnt (HIF-1β) has fueled intensive investigation into the possible crosstalk between oxygen and dioxin signal transduction pathways. Disease Outcomes While disease outcomes associated with 2,4-D exposures continue to be debated, neurotoxic effects have been reported in rats administered high acute doses, possibly as a result of neuronal demyelination. Studies on rats continue to support the view that the hepatotoxic effects of 2,4-D may involve disruption of thiol homeostasis. Reports of kidney and muscle damage have also been published. A case-control study of dogs exposed to 2,4-D in addition to other pesticides used in yard work, reported an increase in lymphomas associated with exposure. Although 2,4-D induced significant numbers of mutations in a Droso-
OCR for page 39
Veterans and Agent Orange: Update 1998 phila cell line and increased mRNA levels of multidrug resistance (mdr) genes in mouse liver, cancer bioassays show no carcinogenic effect. Results from chronic and subchronic toxicity studies indicate that 2,4-D is relatively nontoxic. Limited research has been conducted on the offspring of male animals exposed to herbicides. A study of male mice fed varying concentrations of simulated Agent Orange mixtures concluded there were no adverse effects in offspring. A statistically significant excess of fused sternebra in the offspring of the two most highly exposed groups was attributed to an anomalously low rate of the defect in controls. Another study reported an increase in the incidence of mal-formed offspring of male mice exposed to subacute levels of a mixture of 2,4-D and picloram in drinking water. However, the paternal toxicity observed in the high dosage levels used and inconsistent dose-response pattern are of concern. Limited evidence presented during the past two years suggests that DMA acts as a promoter of urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats. DMA induces apoptosis and sensitizes DNA to oxidative injury. TCDD has been shown to adversely affect a number of organ systems that have been or may be linked to a variety of disease outcomes. TCDD lethality has been associated with changes in brain serotonin metabolism. However, the wide interspecies differences in TCDD-induced lethality cannot be explained by changes in tryptophan metabolism or carbohydrate homeostasis. A prominent symptom of the acute toxicity of TCDD is the loss of adipose tissue and body weight, a phenomenon known as wasting syndrome. Several mechanisms are under investigation including inhibition by TCDD of glucose transport activity and hepatic phosphoenolpyruvate carboxykinase (PEPCK, the rate-limiting enzyme of hepatic gluconeogenesis); the effects of TCDD on adipocyte differentiation; and the effects of TCDD on epidermal growth factor receptor and protein-tyrosine kinase. There is some evidence to suggest that gender differences exist in the response of cells to TCDD. Glucose uptake and lipoprotein lipase activity were significantly decreased in adipose tissue in vitro after intraperitoneal (ip) injection of TCDD in male guinea pigs. No significant effect was observed in females. In addition, radiolabeled-TCDD binding affinity studies in adipose explant tissues showed that tissues from male guinea pigs and monkeys had a higher binding capacity for TCDD than female tissues. TCDD has been shown to induce differentiation in human keratinocytes, which may be initiated by TCDD binding to the AhR. This effect is antagonized by retinoids and may involve interactions between TCDD and retinoids in the regulation of epithelial differentiation. The mechanism by which TCDD induces hepatotoxicity is still under investigation. TCDD has been shown to inhibit hepatocyte DNA synthesis; decrease hepatic plasma membrane epidermal growth factor receptor; inhibit hepatic pyruvate carboxylase activity as a consequence of a reduction in pyruvate carboxylase mRNA levels (this effect was ten-fold greater than in congenic Ahb/b mice, suggesting that a competent AhR is required); and induce cytochrome P4501A1
OCR for page 40
Veterans and Agent Orange: Update 1998 (CYP1A1) in fish and chick embryo hepatocyte cultures, resulting in porphyrin accumulation. Studies have been conducted to examine the short-and long-term effects of TCDD on rat ethoxyresorufin o-deethylase (EROD) activity and liver enzymes. Four days after oral dosing, EROD activity was considerably elevated. Hepatic PEPCK and glutamyl transpeptidase activities were inhibited and stimulated, respectively. Ninety days after dosing, liver EROD activity and PEPCK activity revealed considerable reversibility, whereas glutamyl transpeptidase activity remained elevated. Hepatomegaly has been shown to occur following high subchronic doses. Using Mardin Darvey canine kidney cells, TCDD has been shown to stimulate transcription of the PGHS-2 gene. It has been suggested that PGHS-2 expression may be involved in toxic reactions that involve inappropriate cellular growth, such as tumor promotion. Animal studies and in vitro mechanistic studies continue to emphasize the importance of alterations in neurotransmitter systems as underlying mechanisms of TCDD-induced behavioral dysfunction. Lethal doses of TCDD administered to rats affect the metabolism of serotonin, a neurotransmitter in the brain able to modulate food intake. This biochemical change is consistent with observations of progressive weight loss and anorexia in experimental animals exposed to TCDD. In primary cultures of rat hippocampal neuronal cells, there is evidence that TCDD may increase the uptake of intracellular calcium. This concentration-dependent increase in calcium is associated with a decrease in mitochondrial membrane potentiation and activation of β-protein kinase C (β-PKC). TCDD and structurally related halogenated aromatic hydrocarbons cause a broad range of immunologic effects in experimental animals. Recent studies support earlier data that TCDD decreases innate immunity and host resistance to pathogenic microorganisms; impairs cell-mediated immune responses, such as the generation and lytic activity of cytotoxic T cells; and suppresses humoral immunity by inhibiting B-lymphocyte differentiation into antibody-producing cells. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be mediated primarily through AhR-dependent processes, but some components of immunosuppression have been shown to act independently of the AhR. Low doses of TCDD administered to experimental animals alter reproductive development and fertility of the progeny. Studies in male rats and hamsters have shown that decreased daily sperm production and cauda epididymal sperm number are some of the most sensitive effects of in utero and lactational TCDD exposure. However, in utero and lactational TCDD exposure does not appear to alter radiolabeled sperm transit time through the whole epididymis. Studies have been conducted to determine whether in utero and lactational TCDD exposure decreases male rat accessory sex organ weights during postnatal development and whether this effect involved decreases in testicular androgen production or changes in peripheral androgen metabolism. Results suggest that in utero and
OCR for page 41
Veterans and Agent Orange: Update 1998 lactational TCDD exposure selectively impairs rat prostate growth and development without inhibiting testicular androgen production or consistently decreasing prostate dihydrotestosterone (DHT) concentration. Male mice treated with a mixture of 2,4-D, 2,4,5-T, and TCDD exhibited dose-related liver and thymus toxicity and reduced weight gain, although no significant effects were observed on sperm function, reproductive outcomes, survival of offspring, or neonatal development. In female rats, a single dose of TCDD administered on gestational day (GD) 15 results in malformations of the external genitalia in Long Evans (LE) and Holtzman rats. There was complete to partial clefting of the phallus. Treatment on GD 8 was more effective in inducing functional reproductive alterations in female progeny (e.g., decreased fertility rate, reduced fecundity, cystic endometrial hyperplasia, increased incidence of constant estrus). TCDD administered by gastric intubation altered serum hormone levels in immature female rats. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin levels were increased. This effect is due partially to the action of TCDD on the pituitary and is calcium dependent. After water-borne exposure of newly fertilized eggs to TCDD, the toxicity and histopathology of TCDD in zebrafish revealed that TCDD did not increase egg mortality or affect time to hatching. However, pericardial edema and craniofacial malformations were observed in zebrafish larvae. Reports indicate that in ovo TCDD exposure of the domestic chicken, domestic pigeon, and great blue heron adversely affected the body and skeletal growth and hatchability of the domestic pigeon but had no effect on the domestic chicken or great blue heron. Studies involving human luteinizing granulose cells have shown that glucose transporting activity can be used as a sensitive biomarker to detect the very early response to TCDD in these steroid-producing cells and that the effect of TCDD on progesterone is mediated through cyclic adenosine 5'-monophosphate (cAMP)-dependent protein kinase. TCDD-induced cleft palate and hydronephrosis involve mechanisms that are AhR mediated. There are data to suggest that TCDD interacts with other signaling pathways in inducing cleft palate. For example, cross-regulation of the receptors is believed to be important in the synergistic interaction between TCDD and hydrocortisone. When female mice are treated with TCDD and retinoic acid simultaneously, palatal clefts can be observed in 100 percent of offspring at dose levels far lower than those required for either agent to produce clefting if given alone. This synergy suggests that the pathways controlled by these agents converge at one or more points in cells of the developing palate. The effects of TCDD on the estrogen-signaling system during fetal and perinatal development of peripubertal female rats has been investigated. The mechanism for the reduction in female fertility that accompanies in utero and lactational exposure to TCDD remains unknown, although it could be linked to estrogenic effects such as clefting of the phallus and hypospadias.
OCR for page 42
Veterans and Agent Orange: Update 1998 Several reports published during the reference period describe developmental deficits in the cardiovascular system of TCDD-treated animals. Evidence suggests that the endothelial lining of blood vessels is a primary target site of TCDD-induced cardiovascular toxicity. CYP1A1 is induced in mammalian endothelial cells in culture. The vascular endothelium in lake trout is also uniquely sensitive to induction of CYP1A1 by TCDD in developing animals. CYP1A1 induction in the endothelium may be linked to early lesions that result in TCDD-induced vascular derangements leading to the yolk sac, pericardial, and meningial edema associated with lake trout sac fry mortality. CYP1A1 induction has also been observed in adult quail aortic tissue. The cardiotoxicity induced by TCDD was examined in chick embryo. The spatial and temporal expression of AhR and Arnt suggests that the developing myocardium and cardiac septa are potential targets of TCDD-induced teratogenicity, and such targets are also consistent with cardiac hypertrophy and septal defects observed following TCDD exposure. DNA damage and consequent cell death in the embryonic vasculature are key physiological mediators of TCDD-induced embryotoxicity in medaka (a small Japanese freshwater fish [Oryzias latipes]). Treatment of TCDD-exposed medaka embryos with an antioxidant provides significant protection against TCDD-induced embryotoxicity and suggests that reactive oxygen species may participate in the teratogenic effects of TCDD. TCDD has been shown to significantly induce CYP1A1 mRNA levels and EROD activity in several human cancer cells. Experiments involving several strains of mice provide evidence that a functional Ah receptor is required for TCDD induction of CYP1A1 and liver tumor promotion. However, the AhR does not appear to be exclusively responsible. CYP1A1 induction in various mice strains was not directly related to the degree of tumor-promoting capability, which suggests that other undefined genetic factors may play an important role. Studies comparing liver induction in TCDD-responsive (C57BL/6J) and less responsive (DBA/2J) mice indicate that induction of CYP1B1 and CYP1A1 mRNA content is more pronounced in the former. CYP1A1 was more responsive to TCDD that CYP1B1 in both strains, suggesting that CYP1B1 mRNA expression is less inducible by TCDD but that both genes are AhR regulated. Other studies indicate that the expression of CYP1A1 and CYP1B1 is highly cell specific even though each is regulated through the AhR. However, each P450 exhibits a surprising similar pattern of hormonal regulation even though expressed in different cell types. Studies conducted to compare AhR in cultured fetal cells and adult liver tumors from TCDD-responsive (C57BL/6J) and less responsive (DBA/2J) mice indicate that the responsiveness of fetal cells is likely mediated by the AhR and is not due to a different allelic form of AhR ligand binding subunit in fetal versus adult cells.
OCR for page 113
Veterans and Agent Orange: Update 1998 Diliberto JJ, Jackson JA, Birnbaum LS. 1996. Comparison of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) disposition following pulmonary, oral, dermal, and parenteral exposures to rats. Toxicology and Applied Pharmacology 138:158-168. Dohr O, Sinning R, Vogel C, Munzel P, Abel J. 1997. Effect of transforming growth factor-betal on expression of aryl hydrocarbon receptor and genes of Ah gene battery: clues for independent down-regulation in A549 cells. Molecular Pharmacology 51 (5):703-710. Dohr O, Vogel C, Abel J. 1995. Different response of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive genes in human breast cancer MCF-7 and MDA-MB 231 cells. Archives of Biochemistry and Biophysics 321 (2):405-412. Dolwick KM, Swanson HI, Bradfield CA. 1993. In vitro analysis of Ah receptor domains involved in ligand-activated DNA recognition. Proceedings of the National Academy of Sciences (USA) 90:8566-8570. Duffard R, Garcia G, Rosso S, et al. 1996. Central nervous system myelin deficit in rats exposed to 2,4-dichlorophenoxyacetic acid throughout lactation. Neurotoxicology and Teratology 18:691-696. Dunn RT II, Ruh TS, Burroughs LK, Ruh MF. 1996. Purification and characterization of an Ah receptor binding factor in chromatin. Biochemical Pharmacology 51(4):437-445. Ema M, Ohe N, Suzuki M, Mimura J, Sogawa K, Ikawa S, Fujii-Kuriyama Y. 1994. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. Journal of Biological Chemistry 269(44):27337-27343. Enan E, Matsumura F. 1995a. Evidence for a second pathway in the action mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Significance of Ah-receptor mediated activation of protein kinase under cell-free conditions. Biochemical Pharmacology 49(2):249-261. Enan E, Matsumura F. 1995b. Regulation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) of the DNA binding activity of transcriptional factors via nuclear protein phosphorylation in guinea pig adipose tissue. Biochemical Pharmacology 50:1199-1206. Enan E, Matsumura F. 1996. Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway. Biochemical Pharmacology 52:1599-1612. Enan E, Lasley B, Stewart D, Overstreet J, Vandevoort CA. 1996a. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity. Reproductive Toxicology 10:191-198. Enan E, Moran F, VandeVoort CA, Stewart DR, Overstreet JW, Lasley BL. 1996b. Mechanism of toxic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in cultured human luteinized granulosa cells. Reproductive Toxicology 10:497-508. Enan E, Overstreet JW, Matsumura F, VandeVoort CA, Lasley BL. 1996c. Gender differences in the mechanism of dioxin toxicity in rodents and in nonhuman primates. Reproductive Toxicology 10:401-411. Fan F, Rozman KK. 1995. Short-and long-term biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Long-Evans rats. Toxicology Letters 75:209-216. Fan F, Pinson DM, Rozman KK. 1995. Immunomodulatory effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin tested by the popliteal lymph node assay. Toxicologic Pathology 23(4):513-517. Fan F, Wierda D, Rozman KK. 1996. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on humoral and cell-mediated immunity in Sprague-Dawley rats. Toxicology 106(1-3):221-228. Fan F, Yan B, Wood G, Viluksela M, Rozman KK. 1997. Cytokines (IL-lbeta and TNFalpha) in relation to biochemical and immunological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats. Toxicology 116(1-3):9-16. Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS, Kimura S, Nebert DW, Rudikoff S, Ward JM, Gonzalez FJ. 1995. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor [see comments]. Science 268(5211):722-726.
OCR for page 114
Veterans and Agent Orange: Update 1998 Fiorella PD, Olson JR, Napoli JL. 1995. 2,3,7,8-tetrachlorodibenzo-p-dioxin induces diverse retinoic acid metabolites in multiple tissues of the Sprague-Dawley rat. Toxicology and Applied Pharmacology 134:222-228. Fitzgerald CT, Fernandez-Salguero P, Gonzalez FJ, Nebert DW, Puga A. 1996. Differential regulation of mouse Ah receptor gene expression in cell lines of different tissue origins. Archives of Biochemistry and Biophysics 333(1):170-178. Fukunaga BN, Probst MR, Reisz-Porszasz S, Hankinson O. 1995. Identification of functional domains of the aryl hydrocarbon receptor. Journal of Biological Chemistry 270(49):29270-29278. Gaido KW, Maness SC. 1995. Post-transcriptional stabilization of urokinase plasminogen activator mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin in a human keratinocyte cell line. Toxicology and Applied Pharmacology 133(1):34-42. Gasiewicz TA, Kende AS, Rucci G, Whitney B, Willey JJ. 1996. Analysis of structural requirements for Ah receptor antagonist activity: ellipticines, flavones, and related compounds . Biochemical Pharmacology 52(11):1787-1803. Gassmann M, Kvietikova I, Rolfs A, Wenger RH. 1997. Oxygen-and dioxin-regulated gene expression in mouse hepatoma cells. Kidney International 51(2):567-574. Gebremichael A, Tullis K, Denison MS, Cheek JM, Pinkerton KE. 1996. Ah-receptor-dependent modulation of gene expression by aged and diluted sidestream cigarette smoke. Toxicology and Applied Pharmacology 141(1):76-83. Germolec DR, Adams NH, Luster MI. 1995. Comparative assessment of metabolic enzyme levels in macrophage populations of the F344 rat. Biochemical Pharmacology 50(9):1495-1504. Germolec DR, Henry EC, Maronpot R, Foley JF, Adams NH, Gasiewicz TA, Luster MI. 1996. Induction of CYP1A1 and ALDH-3 in lymphoid tissues from Fisher 344 rats exposed to 2,3,7,8-tetrachlorodibenzodioxin (TCDD). Toxicology and Applied Pharmacology 137(1):57-66. Gilday D, Gannon M, Yutzey K, Bader D, Rifkind AB. 1996. Molecular cloning and expression of two novel avian cytochrome P450 1A enzymes induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Biological Chemistry 271(51):33054-33059. Gohl G, Lehmkoster T, Munzel PA, Schrenk D, Viebahn R, Bock KW. 1996. TCDD-inducible plasminogen activator inhibitor type 2 (PAI-2) in human hepatocytes, HepG2 and monocytic U937 cells. Carcinogenesis 17(3):443-449. Golub MS, Jacobson SW. 1995. Workshop on perinatal exposure to dioxin-like compounds. IV. Neurobehavioral effects. Environmental Health Perspectives 103 (Suppl) 2:151-155. Gonzalez FJ, Fernandez-Salguero P, Lee SS, Pineau T, Ward JM. 1995. Xenobiotic receptor knockout mice. Toxicology Letters 82:83117-83121. Gradin K, McGuire J, Wenger RH, Kvietikova I, Whitelaw ML, Toftgard R, Tora L, Gassmann M, Poellinger L. 1996. Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor. Molecular and Cellular Biology 16(10):5221-5231. Gradin K, Toftgard R, Berghard A. 1995. Differential effects of a topoisomerase I inhibitor on dioxin inducibility and high-level expression of the cytochrome P450IA1 gene. Molecular Pharmacology 48(4):610-615. Gray LE Jr, Kelce WR, Monosson E, Ostby JS, Birnbaum LS. 1995. Exposure to TCDD during development permanently alters reproductive function in male Long-Evans rats and hamsters: reduced ejaculated and epididymal sperm numbers and sex accessory gland weights in offspring with normal androgenic status. Toxicology and Applied Pharmacology 131:108-118. Gray LE Jr, Ostby JS. 1995. In utero 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters reproductive morphology and function in female rat offspring. Toxicology and Applied Pharmacology 133:285-294. Guiney PD, Smolowitz RM, Peterson RE, Stegeman JJ. 1997. Correlation of 2,3,7,8-tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in vascular endothelium with toxicity in early life stages of lake trout. Toxicology and Applied Pharmacology 143(2):256-273.
OCR for page 115
Veterans and Agent Orange: Update 1998 Hahn ME, Chandran K. 1996. Uroporphyrin accumulation associated with cytochrome P4501A induction in fish hepatoma cells exposed to aryl hydrocarbon receptor agonists, including 2,3,7,8-tetrachlorodibenzo-p-dioxin and planar chlorobiphenyls. Archives of Biochemistry and Biophysics 329(2):163-174. Hahn ME, Karchner SI. 1995. Evolutionary conservation of the vertebrate Ah (dioxin) receptor: amplification and sequencing of the PAS domain of a teleost Ah receptor cDNA . Biochemical Journal 310(Pt 2):383-387. Hakkola J, Pasanen M, Pelkonen O, Hukkanen J, Evisalmi S, Anttila S, Rane A, Mantyla M, Purkunen R, Saarikoski S, Tooming M, Raunio H. 1997. Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells. Carcinogenesis 18(2):391-397. Hanberg A, Kling L, Hakansson H. 1996. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hepatic stellate cell population in the rat. Chemosphere 32:1225-1233. Hanneman WH, Legare ME, Barhoumi R, Burghardt RC, Safe S, Tiffany-Castiglioni E. 1996. Stimulation of calcium uptake in cultured rat hippocampal neurons by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology 112:19-28. Harper N, Steinberg M, Thomsen J, Safe S. 1995. Halogenated aromatic hydrocarbon-induced suppression of the plaque-forming cell response in B6C3F1 splenocytes cultured with allogenic mouse serum: Ah receptor structure activity relationships. Toxicology 99(3):199-206. Hassoun EA, Bagchi D, Stohs SJ. 1995. Evidence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced tissue damage in fetal and placental tissues and changes in amniotic fluid lipid metabolites of pregnant CF1 mice. Toxicology Letters 76:245-250. Hassoun EA, Stohs SJ. 1996. Comparative teratological studies on TCDD, endrin and lindane in C57B/6J and DBA/2J mice. Comparative Biochemistry and Physiology: C. Pharmacology, Toxicology, and Endocrinology 113(3)393-398. Hayes HM, Tarone RE, Cantor KP, Jessen CR, McCurnin DM, Richardson RC. 1991. Case-control study of canine malignant lymphoma: positive association with dog owner's use of 2,4-dichlorophenoxyacetic acid herbicides. Journal of the National Cancer Institute 83(17):1226-1231. Hayes HM, Tarone RE, Cantor KP. 1995. On the association between canine malignant lymphoma and opportunity for exposure to 2,4-dichlorophenoxyacetic acid. Environmental Research 70: 119-125. Henry EC, Kent TA, Gasiewicz T. 1997a. DNA binding and transcriptional enhancement by purified TCDD cntdot Ah receptor complex. Archives of Biochemistry and Biophysics 339(2):305-314. Henry TR, Spitsbergen JM, Hornung MW, Abnet CC, Peterson RE. 1997b. Early life stage toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish (Danio rerio). Toxicology and Applied Pharmacology 142:56-68. Henshel DS, Martin JW, Norstrom R, Whitehead P, Steeves JD, Cheng KM. 1995. Morphometric abnormalities in brains of great blue heron hatchlings exposed in the wild to PCDDs. Environmental Health Perspectives 103 (Suppl 4):61-66. Hoffer A, Chang CY, Puga A. 1996. Dioxin induces transcription of fos and jun genes by Ah receptor-dependent and-independent pathways. Toxicology and Applied Pharmacology 141(1): 238-247. Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, Hankinson O. 1991. Cloning of a factor required for activity of the Ah (dioxin) receptor, Science 252(5008):954-958. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA. 1997. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. Journal of Biological Chemistry 272(13):8581-8593. Hossain A, Kikuchi H, Ikawa S, Sagami I, Watanabe M. 1995a. Identification of a 120-kDa protein associated with aromatic hydrocarbon receptor nuclear translocator. Biochemical and Biophysical Research Communications 212(1):144-150.
OCR for page 116
Veterans and Agent Orange: Update 1998 Hossain A, Kikuchi H, Ikawa S, Sagami I, Watanabe M. 1995b. Identification of cellular protein that can interact specifically with the basic helix-loop-helix domain of the aromatic hydrocarbon receptor. Biochemical and Biophysical Research Communications 215(1):405-411. Huang Y, Harper PA, Okey AB. 1995. Aromatic hydrocarbon receptor in cultured fetal cells from C57BL/6J and DBA/2J mice: similarity in molecular mass to receptors in adult livers. Canadian Journal of Physiology and Pharmacology 73(1):18-26. Huff J. 1993. Chemicals and cancer in humans: first evidence in experimental animals. Environmental Health Perspectives 100:201-210. Huff J, Lucier G, Tritscher A. 1994. Carcinogenicity of TCDD: experimental, mechanistic, and epidemiologic evidence. Annual Review of Pharmacology and Toxicology 34:343-372. Hughes MF, Mitchell CT, Edwards BC, Rahman MS. 1995. In vitro percutaneous absorption of dimethylarsinic acid in mice. Journal of Toxicology and Environmental Health 45:279-290. Huisman M, Koopman-Esseboom C, Fidler V, et al. 1995a. Perinatal exposure to polychlorinated biphenyls and dioxins and its effect on neonatal neurological development. Early Human Development 41:111-127. Huisman M, Koopman-Esseboom C, Lanting CI, et al. 1995b. Neurological condition in 18-month-old children perinatally exposed to polychlorinated biphenyls and dioxins. Early Human Development 43:165-176. Hushka DR, Greenlee WF. 1995. 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits DNA synthesis in rat primary hepatocytes. Mutation Research 333:89-99 Ilian MA, Sparrow BR, Ryu BW, Selivonchick DP, Schaup HW. 1996. Expression of hepatic pyruvate carboxylase mRNA in C57BL/6J Ah(b/b) and congenic Ah(d/d) mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Biochemical Toxicology 11:51-56. Janz DM, Bellward GD. 1996a. In ovo 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure in three avian species. 1. Effects on thyroid hormones and growth during the perinatal period. Toxicology and Applied Pharmacology 139:281-291. Janz DM, Bellward GD. 1996b. In ovo 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure in three avian species. 2. Effects on estrogen receptor and plasma sex steroid hormones during the perinatal period. Toxicology and Applied Pharmacology 139:292-300. Jorgensen ECB, Autrnp H. 1995. Effect of a negative regulatory element (NRE) on the human CYP1A1 gene expression in breast carcinoma MCF-7 and hepatoma HepG2 cells. FEBS Letters 365(2-3):101-107. Jorgensen ECB, Autrup H. 1996. Autoregulation of human CYP1A1 gene promoter activity in HepG2 and MCF-7 cells. Carcinogenesis 17(3):435-441. Kale PG, Petty BT Jr, Walker S, Ford JB, Dehkordi N, Tarasia S, Tasie BO, Kale R, Sohni YR. 1995. Mutagenicity testing of nine herbicides and pesticides currently used in agriculture. Environmental and Molecular Mutagenesis 25(2):148-153. Karras JG, Morris DL, Matulka RA, Kramer CM, Holsapple MP. 1996. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elevates basal B-cell intracellular calcium concentration and suppresses surface Ig-but not CD40-induced antibody secretion. Toxicology and Applied Pharmacology 137(2):275-284. Kerkvliet NI. 1995. Immunological effects of chlorinated dibenzo-p -dioxins. Environmental Health Perspectives 103 (Suppl 9):47-53. Kerkvliet NI, Baecher-Steppan L, Shepherd DM, Oughton JA, Vorderstrasse BA, DeKrey GK. 1996. Inhibition of TC-1 cytokine production, effector cytotoxic T lymphocyte development and alloantibody production by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Immunology 157(6):2310-2319. Kharat I, Saatcioglu F. 1996. Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin are mediated by direct transcriptional interference with the liganded estrogen receptor. Cross-talk between aryl hydrocarbon-and estrogen-mediated signaling. Journal of Biological Chemistry 271(18):10533-10537.
OCR for page 117
Veterans and Agent Orange: Update 1998 Kim CS, Binienda Z, Sandberg JA. 1996. Construction of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in the developing rabbit brain. Toxicology and Applied Pharmacology 136:250-259. Kleman M, Gustafsson JA. 1996. Interactions of procarcinogenic heterocyclic amines and indolocarbazoles with the dioxin receptor. Biological Chemistry 377(11):741-762. Ko HP, Okino ST, Ma Q, Whitlock JP Jr. 1996. Dioxin-induced CYP1A1 transcription in vivo: the aromatic hydrocarbon receptor mediates transactivation, enhancer-promoter communication, and changes in chromatin structure. Molecular and Cellular Biology 16(1):430-436 Kohn MC, Lucier GW, Clark GC, Sewall C, Tritscher AM, Portier CJ. 1993. A mechanistic model of effects of dioxin on gene expression in the rat liver. Toxicology and Applied Pharmacology 120(1):138-154. Kohn MC, Sewall CH, Lucier GW, Portier CJ. 1996. A mechanistic model of effects of dioxin on thyroid hormones in the rat. Toxicology and Applied Pharmacology 136:29-48. Kraemer SA, Arthur KA, Denison MS, Smith WL, DeWitt DL. 1996. Regulation of prostaglandin endoperoxide H synthase-2 expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Archives of Biochemistry and Biophysics 330(2):319-328. Kremer J, Lai ZW, Esser C. 1995. Evidence for the promotion of positive selection of thymocytes by Ah receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin. European Journal of Pharmacology 293(4):413-427. Krishnan V, Porter W, Santostefano M, Wang X, Safe S. 1995. Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. Molecular and Cellular Biology 15(12):6710-6719. Lamb JC, Moore JA, Marks TA. 1980. Evaluation of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity in C57BL/6 mice. Reproduction and Fertility in Treated Male Mice and Evaluation of Congenital Malformations in Their Offspring. National Toxicology Program. Lang DS, Becker S, Clark GC, Devlin RB, Koren HS. 1994. Lack of direct immunosuppressive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on human peripheral blood lymphocyte subsets in vitro. Archives of Toxicology 68(5):296-302. Lawrence BP, Leid M, Kerkvliet NI. 1996. Distribution and behavior of the Ah receptor in murine T lymphocytes. Toxicology and Applied Pharmacology 138(2):275-284. Lee IJ, Jeong KS, Roberts BJ, Kallarakal AT, Fernandez-Salguero P, Gonzalez FJ, Song BJ. 1996. Transcriptional induction of the cytochrome p4501al gene by a thiazolium compound, yh439 . Molecular Pharmacology 49(6):980-988. Lesca P, Peryt B, Larrieu G, Alvinerie M, Galtier P, Daujat M, Maurel P, Hoogenboom L. 1995. Evidence for the ligand-independent activation of the ah receptor. Biochemical and Biophysical Research Communications 209(2):474-482. Li SY, Dougherty JJ. 1997. Inhibitors of serine/threonine-specific protein phosphatases stimulate transcription by the Ah receptor/Arnt dimer by affecting a step subsequent to XRE binding. Archives of Biochemistry and Biophysics 340(1):73-82. Li W, Donat S, Dohr O, Unfried K, Abel J. 1994. Ah receptor in different tissues of C57BL/6J and DBA/2J mice: use of competitive polymerase chain reaction to measure Ah-receptor mRNA expression. Archives of Biochemistry and Biophysics 315(2):279-284. Li X, Johnson DC, Rozman KK. 1997. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases release of luteinizing hormone and follicle-stimulating hormone from the pituitary of immature female rats in vivo and in vitro. Toxicology and Applied Pharmacology 142:264-269. Li X, Rozman KK. 1995. Subchronic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and their reversibility in male Sprague-Dawley rats. Toxicology 97:133-140. Lindebro MC, Poellinger L, Whitelaw ML. 1995. Protein-protein interaction via PAS domains: role of the PAS domain in positive and negative regulation of the bHLH/PAS dioxin receptor-Arnt transcription factor complex. EMBO Journal 14(14):3528-35239.
OCR for page 118
Veterans and Agent Orange: Update 1998 Liu H, Safe S. 1996. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on insulin-induced responses in MCF-7 human breast cancer cells. Toxicology and Applied Pharmacology 138(2): 242-250. Liu PC, Matsumura F. 1995. Differential effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the "adipose-type" and "brain-type" glucose transporters in mice. Molecular Pharmacology 47:65-73. Lorenzen A, Kennedy SW, Bastien LJ, Hahn ME. 1997. Halogenated aromatic hydrocarbon-mediated porphyrin accumulation and induction of cytochrome P4501A in chicken embryo hepatocytes. Biochemical Pharmacology 53:373-384. Lorenzen A, Okey AB. 1991. Detection and characterization of Ah receptor in tissue and cells from human tonsils. Toxicology and Applied Pharmacology 107:203-214. Lu YF, Santostefano M, Cunningham BD, Threadgill MD, Safe S. 1996a. Substituted flavones as aryl hydrocarbon (Ah) receptor agonists and antagonists. Biochemical Pharmacology 51(8): 1077-1087. Lu YF, Sun G, Wang X, Safe S. 1996b. Inhibition of prolactin receptor gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in MCF-7 human breast cancer cells. Archives of Biochemistry and Biophysics 332(1):35-40. Luebke RW, Copeland CB, Andrews DL. 1995. Host resistance to Trichinella spiralis infection in rats exposed to 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD). Fundamental and Applied Toxicology 24(2):285-289. Luebke RW, Copeland CB, Diliberto JJ, Akubue PI, Andrews DL, Riddle MM, Williams WC, Birnbaum LS. 1994. Assessment of host resistance to Trichinella spiralis in mice following preinfection exposure to 2,3,7,8-TCDD. Toxicology and Applied Pharmacology 125(1):7-16. Ma Q, Whitlock JP Jr. 1996. The aromatic hydrocarbon receptor modulates the Hepa 1c1c7 cell cycle and differentiated state independently of dioxin. Molecular and Cellular Biology 16(5):2144-2150 Ma X, Stoffregen DA, Wheelock GD, Rininger JA, Babish JG. 1997. Discordant hepatic expression of the cell division control enzyme p34cdc2 kinase, proliferating cell nuclear antigen, p53 tumor suppressor protein, and p21Waf1 cyclin-dependent kinase inhibitory protein after WY14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid) dosing to rats. Molecular Pharmacology 51:69-78. Mahon MJ, Gasiewicz TA. 1995. Ah receptor phosphorylation: localization of phosphorylation sites to the C-terminal half of the protein. Archives of Biochemistry and Biophysics 318(1): 166-174. Masten SA, Shiverick KT. 1995. The Ah receptor recognizes DNA binding sites for the B cell transcription factor, BSAP: a possible mechanism for dioxin-mediated alteration of CD19 gene expression in human B lymphocytes. Biochemical and Biophysical Research Communications 212(1):27-34. Masten SA, Shiverick KT. 1996. Characterization of the aryl hydrocarbon receptor complex in human B lymphocytes: evidence for a distinct nuclear DNA-binding form. Archives of Biochemistry and Biophysics 336(2):297-308. McGrath LF, Cooper KR, Georgopoulos P, Gallo MA. 1995. Alternative models for low dose-response analysis of biochemical and immunological endpoints for tetrachlorodibenzo-p-dioxin. Regulatory Toxicology and Pharmacology 21:382-396. McGuire J, Whitelaw ML, Pongratz I, Gustafsson JA, Poellinger L. 1994. A cellular factor stimulates ligand-dependent release of hsp90 from the basic helix-loop-helix dioxin receptor. Molecular and Cellular Biology 14(4):2438-2446. Mekenyan OG, Veith GD, Call DJ, Ankley GT. 1996. A QSAR evaluation of Ah receptor binding of halogenated aromatic xenobiotics. Environmental Health Perspectives 104(12):1302-1310. Merchant M, Safe S. 1995. In vitro inhibition of 2,3,7,8 -tetrachlorodibenzo-p-dioxin-induced activity by alpha-naphthoflavone and 6-methyl-1,3,8-trichlorodibenzofuran using an aryl hydrocarbon (Ah)-responsive construct. Biochemical Pharmacology 50(5):663-668.
OCR for page 119
Veterans and Agent Orange: Update 1998 Michalek JE, Caudill SP, Tripathi RC. 1997. Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 10-year follow-up. Erratum. Journal of Toxicology and Environmental Health 52(6):557-558. Michalek JE, Pirkle JL, Caudill SP, Tripathi RC, Patterson DG Jr, Needham LL. 1996a. Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 10-year follow-up. Journal of Toxicology and Environmental Health 47:209-220. Michalek JE, Tripathi RC, Kulkarni PM, Pirkle JL. 1996b. The reliability of the serum dioxin measurement in veterans of Operation Ranch Hand. Journal of Exposure Analysis and Environmental Epidemiology 6:327-338. Miranda S, Vollrath V, Wielandt AM, Loyola G, Bronfman M, Chianale J. 1997. Overexpression of mdr2 gene by peroxisome proliferators in the mouse liver. Journal of Hepatology 26(6): 1331-1339. Moos AB, Kerkvliet NI. 1995. Inhibition of tumor necrosis factor activity fails to restore 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced suppression of the antibody response to sheep red blood cells. Toxicology Letters 81(2-3):175-181. Mufti NA, Bleckwenn NA, Babish JG, Shuler ML. 1995. Possible involvement of the Ah receptor in the induction of cytochrome P-450IA1 under conditions of hydrodynamic shear in microcarrier-attached hepatoma cell lines. Biochemical and Biophysical Research Communications 208(1):144-152. Mýnzel P, Bock-Hennig B, Schieback S, Gschaidmeier H, Beck-Gschaidmeier S, Bock KW. 1996. Growth modulation of hepatocytes and rat liver epithelial cells (WB-F344) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Carcinogenesis 17(2):197-202. Neubert R, Maskow L, Delgado I, Helge H, Neubert D. 1995. Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 2. In vitro proliferation of lymphocytes from workers with quantified moderately-increased body burdens. Life Sciences 56(6): 421-436. Nodland KI, Wormke M, Safe S. 1997. Inhibition of estrogen-induced activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the MCF-7 human breast cancer and other cell lines transfected with vitellogenin A2 gene promoter constructs. Archives of Biochemistry and Biophysics 338(1):67-72. Ochi T, Nakajima F, Sakurai T, Kaise T, Oya-Ohta Y. 1996. Dimethylarsinic acid causes apoptosis in HL-60 cells via interaction with glutathione. Archives of Toxicology 70:815-821. Okino ST, Whitlock JP Jr. 1995. Dioxin induces localized, graded changes in chromatin structure: implications for Cyp1A1 gene transcription. Molecular and Cellular Biology 15(7):3714-3721. Oliveira GH, Palermo-Neto J. 1995. Toxicology of 2,4-dichlorophenoxyacetic acid (2,4-D) and its determination in serum and brain tissue using gas chromatography-electron-capture detection. Journal of Analytical Toxicology 19:251-255. Olnes MJ, Verma M, Kurl RN. 1996. 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates expression of the prostaglandin G/H synthase-2 gene in rat thymocytes. Journal of Pharmacology and Experimental Therapeutics 279(3):1566-1573. Ou X, Ramos KS. 1995. Regulation of cytochrome P4501A1 gene expression in vascular smooth muscle cells through aryl hydrocarbon receptor-mediated signal transduction requires a protein synthesis inhibitor. Archives of Biochemistry and Biophysics 316(1):116-122. Palmeira CM, Moreno AJ, Madeira VM. 1995a. Effects of paraquat, dinoseb and 2,4-D on intracellular calcium and on vasopressin-induced calcium mobilization in isolated hepatocytes. Archives of Toxicology 69:460-466. Palmeira CM, Moreno AJ, Madeira VM. 1995b. Thiols metabolism is altered by the herbicides paraquat, dinoseb and 2,4-D: a study in isolated hepatocytes. Toxicology Letters 81:115-123.
OCR for page 120
Veterans and Agent Orange: Update 1998 Park JY, Shigenaga MK, Ames BN. 1996. Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo (3,2-b) carbazole is associated with oxidative DNA damage. Proceedings of the National Academy of Sciences of the United States of America 93(6): 2322-2327. Paulino CA, Guerra JL, Oliveira GH, Palermo-Neto J. 1996. Acute, subchronic and chronic 2,4-dichlorophenoxyacetic acid (2,4-D) intoxication in rats. Veterinary and Human Toxicology 38:348-352. Paulino CA, Palermo-Neto J. 1995. Effects of acute 2.4-dichlorophenoxyacetic acid on cattle serum components and enzyme activities. Veterinary and Human Toxicology 37:329-332. Peters JM, Wiley LM. 1995a. Murine preimplantation embryos express aryl hydrocarbon receptor nuclear translocator (Arnt) mRNA. Teratology 51(3):193. Peters JM, Wiley LM. 1995b. Evidence that murine preimplantation embryos express aryl hydrocarbon receptor. Toxicology and Applied Pharmacology 134(2):214-221. Phillips M, Enan E, Liu PC, Matsumura F. 1995. Inhibition of 3T3-L1 adipose differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Cell Science 108(Pt 1):395-402. Pohl H. Holler J. 1995. Halogenated aromatic hydrocarbons and toxicity equivalency factors (TEFs) from the public health assessment perspective. Chemosphere 31(1):2547-2559. Pollenz RS, Sullivan HR. Holmes J, Necela B, Peterson RE. 1996. Isolation and expression of cDNAs from rainbow trout (Oncorhynchus mykiss) that encode two novel basic helix-loop-Helix/PER-ARNT-SIM (bHLH/PAS) proteins with distinct functions in the presence of the aryl hydrocarbon receptor. Evidence for alternative mRNA splicing and dominant negative activity in the bHLH/PAS family. Journal of Biological Chemistry 271(48):30886-30896. Prell RA, Kerkvliet NI. 1997. Involvement of altered B7 expression in dioxin immunotoxicity: B7 transfection restores the CTL but not the autoantibody response to the P815 mastocytoma. Journal of Immunology 158(6):2695-2703. Prell RA, Oughton JA, Kerkviet NI. 1995. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on anti-CD3-induced changes in T-cell subsets and cytokine production. International Journal of Immunopharmacology 17(11):951-961. Rhile MJ, Nagarkatti M, Nagarkatti PS. 1996. Role of Fas apoptosis and MHC genes in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity of T cells. Toxicology 110(1-3):153-167. Rier SE, Martin DC, Bowman RE, Dmowski WP, Becker JL. 1993. Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin [see comments]. Fundamental and Applied Toxicology 21(4):433-441. Rin K, Kawaguchi K, Yamanaka K, Tezuka M, Oku N, Okada S. 1995. DNA-strand breaks induced by dimethylarsinic acid, a metabolite of inorganic arsenics, are strongly enhanced by superoxide anion radicals. Biological and Pharmaceutical Bulletin 18:45-48. Roman BL, Sommer RJ, Shinomiya K, Peterson RE. 1995. In utero and lactational exposure of the male rat to 2,3,7,8-tetrachlorodibenzo-p-dioxin: impaired prostate growth and development without inhibited androgen production. Toxicology and Applied Pharmacology 134:241-250. Ross PS, De Swart RL, Timmerman HH, Reijnders PJH, Vos JG, Van Loveren H, Osterhaus ADME. 1996. Suppression of natural killer cell activity in harbour seals (Phoca vitulina) fed Baltic Sea herring. Aquatic Toxicology 34(1):71-84. Rowlands JC, McEwan IJ, Gustafsson JA. 1996. Trans-activation by the human aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator proteins: direct interactions with basal transcription factors. Molecular Pharmacology 50(3):538-548. Sadar MD, Ash R, Sundqvist J, Olsson PE, Andersson TB. 1996a. Phenobarbital induction of CYPIA1 gene expression in a primary culture of rainbow trout hepatocytes. Journal of Biological Chemistry 271(30):17635-17643.
OCR for page 121
Veterans and Agent Orange: Update 1998 Sadar MD, Blomstrand F, Andersson TB. 1996b. Phenobarbital induction of cytochrome P4501A1 is regulated by cAMP-dependent protein kinase-mediated signaling pathways in rainbow trout hepatocytes . Biochemical and Biophysical Research Communications 225(2):455-461. Sadar MD, Westlind A, Blomstrand F, Andersson TB. 1996c. Induction of CYP1A1 by GABA receptor ligands. Biochemical and Biophysical Research Communications 229(1):231-237. Sandberg JA, Duhart HM, Lipe G, Binienda Z, Slikker W Jr, Kim CS. 1996. Distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) in maternal and fetal rabbits. Journal of Toxicology and Environmental Health 49:497-509. Sanderson JT, Aarts JM, Brouwer A, Froese KL, Denison MS, Giesy JP. 1996. Comparison of Ah receptor-mediated luciferase and ethoxyresorufin-O-deethylase induction in H4IIE cells: implications for their use as bioanalytical tools for the detection of polyhalogenated aromatic hydrocarbons. Toxicology and Applied Pharmacology 137(2):316-325. Santostefano M, Safe S. 1996. Characterization of the molecular and structural properties of the transformed and nuclear aryl hydrocarbon (Ah) receptor complexes by proteolytic digestion. Chemico-Biological Interactions 100(3):221-240. Sastry BV, Janson VE, Clark CP, Owens LK. 1997. Cellular toxicity of 2,4,5-trichlorophenoxyacetic acid: formation of 2,4,5-trichlorophenoxyacetylcholine. Cellular and Molecular Biology 43(4):549-557. Schmidt JV, Bradfield CA. 1996. Ah receptor signaling pathways. Annual Review of Cell and Developmental Biology 12:55-89. Schmidt JV, Su, GH, Reddy JK, Simon MC, Bradfield CA. 1996. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proceedings of the National Academy of Sciences of the United States of America 93(13):6731-6736. Schuetz EG, Schuetz JD, Thompson MT, Fisher RA, Madariage JR, Strom SC. 1995. Phenotypic variability in induction of P-glycoprotein mRNA by aromatic hydrocarbons in primary human hepatocytes. Molecular Carcinogenesis 12(2):61-65. Selmin O, Lucier GW, Clark GC, et al. 1996. Isolation and characterization of a novel gene induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver. Carcinogenesis 17:2609-2615. Sewall CH, Clark GC, Lucier GW. 1995a. TCDD reduces rat hepatic epidermal growth factor receptor: comparison of binding, immunodetection, and autophosphorylation . Toxicology and Applied Pharmacology 132:263-272. Sewall CH. Flagler N, Vanden Heuvel JP, et al. 1995b. Alterations in thyroid function in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 132:237-244. Smialowicz RJ, Williams WC, Riddle MM. 1996. Comparison of the T cell-independent antibody response of mice and rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundamental and Applied Toxicology 32(2):293-297. Sommer R J, Ippolito DL, Peterson RE. 1996. In utero and lactational exposure of the male Holtzman rat to 2,3,7,8-tetrachlorodibenzo-p-dioxin: decreased epididymal and ejaculated sperm numbers without alterations in sperm transit rate. Toxicology and Applied Pharmacology 140:146-153. Stahl BU. 1995. 2,3,7,8-tetrachlorodibenzo-p-dioxin blocks the physiological regulation of hepatic phosphoenolpyruvate carboxykinase activity in primary rat hepatocytes. Toxicology 103:45-52. Stegeman JJ, Hahn ME, Weisbrod R, Woodin BR, Joy JS, Najibi S, Cohen RA. 1995. Induction of cytochrome P4501A1 by aryl hydrocarbon receptor agonists in porcine aorta endothelial cells in culture and cytochrome P4501A1 activity in intact cells. Molecular Pharmacology 47(2):296-306. Swanson HI, Chan WK, Bradfield CA. 1995. DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins. Journal of Biological Chemistry 270(44):26292-26302.
OCR for page 122
Veterans and Agent Orange: Update 1998 Tritscher AM. Seacat AM, Yager JD, et al. 1996. Increased oxidative DNA damage in livers of 2,3,7,8-tetrachlorodibenzo-p-dioxin treated intact but not ovariectomized rats. Cancer Letters 98:219-225. Tuomisto J, Andrzejewski W, Unkila M, et al. 1995. Modulation of TCDD-induced wasting syndrome by portocaval anastomosis and vagotomy in Long-Evans and Han/Wistar rats. European Journal of Pharmacology 292:277-285. Unkila M, Pohjanvirta R, Tuomisto J. 1995a. Biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds on the central nervous system. International Journal of Biochemistry and Cell Biology 27:443-455. Unkila M, Ruotsalainen M, Pohjanvirta R, et al. 1995b. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on tryptophan and glucose homeostasis in the most TCDD-susceptible and the most TCDD-resistant species, guinea pigs and hamsters. Archives of Toxicology 69:677-683. Van Birgelen AP, Van der Kolk J, Fase KM, et al. 1995. Subchronic dose-response study of 2.3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats. Toxicology and Applied Pharmacology 132:1-13. Vasiliou V, Kozak CA, Lindahl R, Nebert DW. 1996. Mouse microsomal class 3 aldehyde dehydro-genase: AHD3 cDNA sequence, inducibility by dioxin and clofibrate, and genetic mapping. DNA and Cell Biology 15(3):235-245. Viluksela M, Stahl BU, Rozman KK. 1995. Tissue-specific effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in rats. Toxicology and Applied Pharmacology 135:308-315. Voskoboinik I, Ooi SG, Drew R, Ahokas JT. 1997. Peroxisome proliferators increase the formation of BPDE-DNA adducts in isolated rat hepatocytes. Toxicology 122(1-2):81-91. Walker MK, Cook PM, Butterworth BC, Zabel EW, Peterson RE. 1996. Potency of a complex mixture of polychlorinated dibenzo-p-dioxin, dibenzofuran, and biphenyl congeners compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin in causing fish early life stage mortality. Fundamental and Applied Toxicology 30:178-186. Walker MK, Pollenz RS, Smith SM. 1997. Expression of the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator during chick cardiogenesis is consistent with 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced heart defects . Toxicology and Applied Pharmacology 143(2):407-419. Walsh AA, Tullis K, Rice RH, Denison MS. 1996. Identification of a novel cis-acting negative regulatory element affecting expression of the CYP1A1 gene in rat epidermal cells. Journal of Biological Chemistry 271(37):22746-22753. Wang X, Thomsen JS, Santostefano M, Rosengren R, Safe S, Perdew GH. 1995. Comparative properties of the nuclear aryl hydrocarbon (Ah) receptor complex from several human cell lines. European Journal of Pharmacology 293(3):191-205. Wanibuchi H, Yamamoto S, Chen H, et al. 1996. Promoting effects of dimethylarsinic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats. Carcinogenesis 17:2435-2439. Wanner R, Brommer S, Czarnetzki BM, Rosenbach T. 1995. The differentiation-related upregulation of aryl hydrocarbon receptor transcript levels is suppressed by retinoic acid. Biochemical and Biophysical Research Communications 209(2):706-711. Wanner R, Panteleyev A, Henz BM, Rosenbach T. 1996. Retinoic acid affects the expression rate of the differentiation-related genes aryl hydrocarbon receptor, ARNT and keratin 4 in proliferative keratinocytes only . Biochimica et Biophysica Acta 1317(2):105-111. Wamgard L, Bager Y, Kato Y, Kenne K, Ahlborg UG. 1996. Mechanistical studies of the inhibition of intercellular communication by organochlorine compounds. Archives of Toxicology Supplement 18:149-159.
OCR for page 123
Veterans and Agent Orange: Update 1998 Watson MA, Devereux TR, Malarkey DE, Anderson MW, Maronpot RR. 1995. H-ras oncogene mutation spectra in B6C3F1 and C57BL/6 mouse liver tumors provide evidence for TCDD promotion of spontaneous and vinyl carbamate-initiated liver cells. Carcinogenesis 16(8): 1705-1710. Weber LW, Lebofsky M, Stahl BU, Smith S, Rozman KK. 1995. Correlation between toxicity and effects on intermediary metabolism in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male C57BL/ 6J and DBA/2J mice. Toxicology and Applied Pharmacology 131:155-162. Weiss C, Kolluri SK, Kiefer F, Gottlicher M. 1996. Complementation of Ah receptor deficiency in hepatoma cells: negative feedback regulation and cell cycle control by the Ah receptor. Experimental Cell Research 226(1 ):154-163. Weston WM, Nugent P, Greene RM. 1995. Inhibition of retinoic-acid-induced gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin . Biochemical and Biophysical Research Communications 207(2):690-694. White TE, Rucci G, Liu Z, Gasiewicz TA. 1995. Weanling female Sprague-Dawley rats are not sensitive to the antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicology and Applied Pharmacology 133(2):313-320. Whitelaw ML, McGuire J, Picard D, Gustafsson JA, Poellinger L. 1995. Heat shock protein hsp90 regulates dioxin receptor function in vivo. Proceedings of the National Academy of Sciences of the United States of America 92(10):4437-4441. Wilker C, Johnson L, Safe S. 1996. Effects of developmental exposure to indole-3-carbinol or 2,3,7,8-tetrachlorodibenzo-p-dioxin on reproductive potential of male rat offspring. Toxicology and Applied Pharmacology 141(1):68-75. Wolfle D, Marquardt H. 1996. Antioxidants inhibit the enhancement of malignant cell transformation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Carcinogenesis 17:1273-1278. Xiao GH, Pinaire JA, Rodrigues AD, Prough RA. 1995. Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes. Drug Metabolism and Disposition 23(6):642-650. Yamaguchi Y, Kuo MT. 1995. Functional analysis of aryl hydrocarbon receptor nuclear translocator interactions with aryl hydrocarbon receptor in the yeast two-hybrid system. Biochemical Pharmacology 50(8):1295-1302. Yamamoto S, Wanibuchi H, Hori T, Yano Y, Matsui-Yuasa I, Otani S, Chen H. Yoshida K, Kuroda K, Endo G, Fukushima S. 1997. Possible carcinogenic potential of dimethylarsinic acid as assessed in rat in vivo models: a review. Mutation Research 386(3):353-361. Yao Y, Hoffer A, Chang CY, Puga A. 1995. Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme. Environmental Health Perspectives 103(4):366-371. Zhao W, Ramos KS. 1995. Inhibition of DNA synthesis in primary cultures of adult rat hepatocytes by benzo[a]pyrene and related aromatic hydrocarbons: role of Ah receptor-dependent events. Toxicology 99(3):179-189. Zorn NE, Russell DH, Buckley AR, Sauro MD. 1995. Alterations in splenocyte protein kinase C (PKC) activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in vivo. Toxicology Letters 78:93-100.
Representative terms from entire chapter: