Hypothalamic site of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Administration of TCDD produced a significant decrease in the serum concentration of prolactin (PRL) detected in rats after 4 hr compared to pair-fed vehicle controls and noninjected controls. This effect of TCDD was reversed by pimozide, a dopamine receptor antagonist. These data suggest that TCDD decreased the release of PRL from the adenohypophysis either by a direct effect on the gland or by altering the dopamine concentration in the median eminence (ME). Concentrations of TCDD from 5 to 500 ng/ml had no direct effect on the ability of the adenohypophysis to secrete PRL in vitro. However, the dopamine concentration increased to 3.24 +/- 0.07 ng per ME in TCDD-treated rats compared to 2.81 +/- 0.08 ng in vehicle controls. This is a dramatic alteration in the dopamine concentration, since the dopamine is being measured in the portal circulation which exhibits a rapid turnover. The rate constant of dopamine depletion after alpha-methyl-p-tyrosine and the turnover rate were also significantly elevated in the ME of TCDD-treated rats. These data provide the first biochemical evidence for a hypothalamic site of action of TCDD. Since dopamine is inhibitory to PRL release from the adenohypophysis, increased ME steady-state concentrations and turnover of this catecholamine may be responsible for the decreased concentration of serum PRL detected within 4 hr of TCDD injection. Thus, one of the early modes and sites of action of TCDD is to elevate the dopaminergic activity of the tuberoinfundibular nucleus. A hypothalamic site of action for TCDD may result in a number of the endocrinological effects known to be produced by exposure to TCDD.     

Evidence for direct action of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on thymic epithelium

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts on selected targets within the immune system to produce a characteristic profile of pathologic responses typified by thymic atrophy, suppressed cellular immunity, and inhibition of antibody production to T-lymphocyte-dependent antigens. Studies in inbred mice differing in sensitivity to TCDD indicate that TCDD-induced thymic atrophy is mediated by a receptor protein (designated the Ah receptor). To study the cellular and molecular basis for TCDD-induced thymic atrophy, primary cultures of thymic epithelial (TE) cells were established from C57BL/6 mice, a strain sensitive to TCDD. Treatment of TE monolayers with TCDD (0.1 to 10 nM) resulted in the altered maturation of cocultured syngeneic thymocytes as judged by suppression (40% of control at 10 nM TCDD) of TE-dependent responsiveness of thymocytes to the mitogens concanavalin A and phytohemagglutinin. TE-conditioned medium enhanced the mitogen responsiveness of thymocytes three- to four-fold; however, the enhanced mitogen response mediated by the TE-conditioned medium was not suppressed in thymocytes incubated in medium collected from TCDD-treated cultures or in TE-conditioned medium to which TCDD (10 nM) had been added directly. The suppression of TE-dependent maturation of thymocytes was concentration dependent (EC50 approximately 1 nM) and stereospecific, suggesting involvement of the Ah receptor. The Ah receptor in cytosol fractions from cultured TE cells was measured directly and was found to be present at a concentration 3 and 3.5 times greater than that measured in whole thymus and thymocytes, respectively. The results of this study indicate that TCDD can act directly on epithelial target cells in the thymus: one consequence of this action appears to be the altered thymus-dependent maturation of T-lymphocyte precursors, mediated through direct cell-cell contact between thymocytes and TE cells.     

Regulation of polyamine biosynthesis by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

We have examined the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on tissue polyamine concentrations in CD1 mice. Two days after a low dose treatment with TCDD, polyamine content of the liver and thymus of treated mice showed a 49-82% decrease, but that of spleen was not affected. Based on this finding, we examined the role of alterations in polyamine levels in the toxicity of TCDD. We administered the polyamine biosynthetic inhibitor difluoromethylornithine (DFMO) to animals treated with a toxic dose of TCDD. DFMO dramatically increased the toxicity of TCDD as measured by mortality, ascites and changes in organ weights. In addition, administration of the polyamine putrescine was able to reduce the toxicity of TCDD. These results suggest that a decrease in polyamine concentrations in critical organs may play an important role in the toxic effects of TCDD.     

Percutaneous absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) from soil

Eight dermal absorption experiments (two in vivo; six in vitro) and one intravenous experiment were conducted using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) either neat (high dose at approximately 250 microg/cm(2) and low dose at 10 ng/cm(2)) or sorbed on a low organic soil (LOS) or high organic soil (HOS) at 1 ppm (10 ng TCDD/10 mg soil/cm(2)). After 96 h the percent of applied dose absorbed (PADA) for the neat low dose was 78% in vivo (rat) and 76% in vitro (rat). PADA for the equivalent TCDD dose sorbed on LOS were 16.3% (rat in vivo), 7.7% (rat in vitro) and 2.4% (human in vitro). The PADA for TCDD sorbed on HOS (1 ppm) was 1.0% (rat in vitro). Generally, rat skin was observed to be three to four times more permeable to TCDD than human skin. At steady state, the dermal flux of TCDD in neat form, sorbed on LOS at 1 ppm, and sorbed on HOS at 1 ppm (all in vitro, rat) was 120, 0.007, and 0.0007 ng/cm(2)/h, respectively (ratio = 1.7 x 10(5):10:1). Making adjustments to account for differences between in vitro and in vivo results and adjusting for application to monolayer loads, the 24-h TCDD absorption for human skin is estimated as 1.9% from LOS (1 ppm) and 0.24% from HOS (1 ppm).     

Reduced gluconeogenesis in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats

The effect of a usually lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 125 g/kg) was studied on the conversion of¹⁴C-alanine into¹⁴C-glucose in male Sprague-Dawley rats by established procedures (determination of plasma alanine and blood glucose by enzymatic assays and isolation of¹⁴C-alanine and¹⁴C-glucose from whole blood by column chromatography). TCDD-treated rats converted significantly (p < 0.05) less¹⁴C-alanine into¹⁴C-glucose than did their pair-fed or ad libitum-fed counterparts, indicating reduced gluconeogenesis as a result of TCDD treatment. This finding suggests that reduced gluconeogenesis in TCDD-treated rats contributed to the progressively developing, severe hypoglycemia observed in these animals. Corticosterone, a key hormone in gluconeogenesis, provides partial protection from TCDD-induced toxicity in hypophysectomized rats. Therefore, the conversion of¹⁴C-alanine into¹⁴C-glucose was also determined in hypophysectomized rats dosed with TCDD (125 g/kg) and given corticosterone (25 g/ ml in drinking water). These rats also converted significantly (p <0.05) less¹⁴C-alanine into¹⁴C-glucose than did their pair-fed counterparts. However, in contrast to non-hypophysectomized TCDD-treated rats, these rats maintained marginal normoglycemia even at 64 days after dosing with TCDD, which suggests that the partial protective effect of corticosterone in hypophysectomized, TCDD-treated rats is unrelated to its effect on gluconeogenesis. The protection provided by corticosterone supplementation in TCDD toxicity is more likely due to reduced peripheral utilization of glucose enabling the animals to maintain marginal normoglycemia.Presented in part at the 27th Annual Meeting of the Society of Toxicology, Dallas, TX, 1988     

Quantitative cancer risk assessments for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

State-of-the-art quantitative risk assessment techniques, including consideration of new time-to-response data, have been applied to chronic animal bioassay data on the dietary intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The non-linear shapes of the dose-response relationships for the hepatocellular carcinogenic responses have been estimated, and a review of the quantitative impacts of several of the choices involved in the quantitative risk assessment considers, particularly, the definition of the carcinogenic responses of concern, the experimental data set, the pathology evaluation, a biologically effective dose scale versus the administered dose, methods of making the fitted model responsive to the data at the lower experimental doses, consistency in dose-response shapes for different data sets, fitted model values versus bounds, the utilization of time-to-response information incorporating the lateness of the carcinogenic responses, and the method of characterizing the maximum acceptable dose. The estimated virtually safe dose for an increase of 0.000001 (one in a million) in the probability of hepatocellular neoplastic nodule and/or carcinoma in a female rat is approximately 0.1 ng/kg body weight/day in the diet. The estimated mean free dose, corresponding to a reduction in the expected amount of time without hepatocellular neoplastic nodule and/or carcinoma proportional to 1 wk in 70 yr, is in the range of 1-5 ng/kg body weight/day in the diet of a female rat. No species-to-species extrapolations nor human exposure assessments have been made. However, these estimated risks correspond to dietary intakes that are at least 150 times greater than the 0.0006365 ng/kg body weight/day intake described by the Centers for Disease Control as a reasonable level to begin consideration of action to limit human exposure.     

Rabbit serum hypertriglyceridemia after administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) caused a dose-dependent decrease of adipose tissue lipoprotein lipase (LPL) activity and caused a concomitant increase in serum triglyceride concentration in the rabbit 10 d after single ip administration of either 1 or 50 micrograms/kg. Hepatic low-density lipoprotein (LDL) binding was markedly depressed and serum cholesterol concentrations were modestly increased relative to pair-fed control animals. Serum glucose concentrations were significantly lower in the rabbit administered TCDD compared to ad libitum or pair-fed control animals, although little change was observed in serum insulin concentration. Electron microscopic examination of aortic arches 20 d after a single ip administration of 50 micrograms TCDD/kg revealed ruffling, denudation, and sloughing off of the cell surface and the appearance of macrophage-like structures in the intima and media of the endothelial cells. These alterations resemble preatherosclerotic lesions typical in animals with hyperlipidemia. It is proposed that TCDD causes hyperlipidemia in the rabbit through suppression of LPL activity and LDL receptor binding.     

Thyroid hormones modulate the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

These experiments examine the role of thyroxine (T4) and triiodothyronine (T3) on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The first experiment is continuation of a study reported previously (Rozman et al., 1984). In this experiment, 60 male Sprague-Dawley rats were divided into 6 equal groups. Four groups of rats were thyroidectomized by 3 mCi Na131 l/kg rat. Five weeks later 2 of the thyroidectomized and 1 of the nonthyroidectomized groups of rats received ip 100 micrograms TCDD/kg body weight in corn oil/acetone, whereas 3 corresponding groups of rats served as vehicle controls. Two days after dosing and every 7 d thereafter, 1 thyroidectomized control group and 1 thyroidectomized TCDD-dosed group were given ip 105 micrograms T4/kg body weight. Mortality and body weight were monitored. The course of TCDD toxicity was similar in nonthyroidectomized and thyroidectomized T4-treated rats but was different in thyroidectomized animals without T4 replacement therapy. At d 90 after TCDD dosage, mortality was still lower and the mean time to death was increased (p less than 0.01) in this group of rats compared to nonthyroidectomized or thyroidectomized T4-treated rats. However, administration of T4 starting at d 91 after dosing with TCDD resulted within 2 wk in the same final mortality in thyroidectomized rats as in nonthyroidectomized or thyroidectomized T4-treated animals, indicating that thyroid hormones modulate the time course of the wasting syndrome but do not affect the ultimate mortality figure. Body weight loss was much slower in thyroidectomized (approximately 1 g/d) than in nonthyroidectomized or thyroidectomized T4-treated rats (approximately 8 g/d). In the second experiment the three vehicle control groups of the first experiment were used. Nonthyroidectomized vehicle controls and thyroidectomized T4-treated controls were maintained as before, whereas thyroidectomized controls received T3 at 5 micrograms/kg daily. One month later each rat was dosed with TCDD at 100 micrograms/kg in corn oil/acetone. Toxicity of TCDD was similar in nonthyroidectomized, thyroidectomized T4-treated, and thyroidectomized T3-treated rats as judged by mortality, body weight, and food intake, indicating no difference between T3 and T4 in the modulation of TCDD toxicity.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on preimplantation mouse embryos

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental contaminant that can exert developmental toxicity. To investigate the stage-specific effects of TCDD on preimplantation embryos, we exposed mouse embryos to TCDD at different stages (1-, 2-, and 8-cell) and collected them at different stages of development (the 1- or 2-, 8-cell, and blastocyst stage, respectively). Semiquantitative RT-PCR revealed increased constitutive gene expression of the arylhydrocarbon receptor (AhR) and AhR nuclear translocator (Arnt) at the 1-cell stage, decreased expression at the 2- to 8-cell stage, and increased expression again at the blastocyst stage, and addition of TCDD to media did not affect their mRNA levels. Interestingly, no cytochrome P4501A1 (CYP1A1) mRNA was detected in embryos at the 1-, 2-, and 8-cell stages after exposure to 10 nM TCDD for 12 or 24 h, whereas CYP1A1 mRNA was significantly increased at the blastocyst stage in response to TCDD, and its induction was found to be concentration-dependent on TCDD exposure from 0.01 to 10 nM for 24 h. In addition, no significant differences in development rate of preimplantation embryos, cell number of blastocyst embryos, or apoptotic indices, such as TUNEL-positive cell number or Bax/Bcl-2 expression ratios were observed at the blastocyst stage between TCDD-exposed groups and non-exposed group. These results suggest that the sensitivity to TCDD differs with the embryonic stage, which may reflect an ability of embryos to adapt to environmental stressors, such as dioxins.     

Learning in monkeys exposed perinatally to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

TCDD is an extremely toxic chemical pollutant which bioaccumulates in maternal adipose tissue, and is transferred to the developing organism during gestation and lactation. Long-term cognitive deficits have been reported following perinatal exposure to polychlorinated biphenyls, which are structurally and toxicologically similar to TCDD. In the current study, monkeys exposed to TCDD perinatally were later tested in two cognitive paradigms, discrimination-reversal learning (RL) and delayed spatial alternation (DSA). RL detected effects; whereas DSA, as analyzed, did not. RL consisted of a series of simple spatial reversals, followed by spatial reversals with color and shape as irrelevant cues, then by color reversals and finally by shape reversals. TCDD-exposed monkeys exhibited retarded learning of the shape reversals. The deficit was most pronounced on the first reversal following overtraining. There were no group differences on the spatial or color reversals. However, the number of trials the TCDD-exposed monkeys individually took to learn the spatial reversals was positively correlated with TCDD concentration in body fat. Conversely, the number of trials they took to learn the color reversals was negatively correlated with TCDD in body fat.     

Absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after low dose dermal exposure

Human dermal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) occurs through contact with soil and paper products. In a previous study, relative percutaneous absorption of TCDD increased as the dose decreased (Brewster et al., 1989). To determine the rate of absorption of a low dose of TCDD, absorption, distribution, and elimination were examined at 1, 4, 8, 12, 24, 48, 72, and 120 hr after dermal application of 200 pmol (111 pmol/cm2) [3H]TCDD to 10-week-old male Fischer 344 rats. The compound was applied over a 1.8 cm2 area of the interscapular region of the back in 60 microliters acetone and covered with a perforated cap; animals were held in individual metabolism cages. Within 120 hr after dosing, 82 pmol (26 ng) of TCDD was absorbed. Absorption kinetics appeared to be first-order; the absorption rate constant was 0.005 hr-1. At each time point, greater than 70% of the radioactivity detected in the application site could be removed by swabbing with acetone. The time-related increase in the amount of TCDD in liver and fat closely paralleled the amount absorbed, while the percentage of the administered dose detected in the blood was never greater than 0.3%. Thus, absorption of a low dose of TCDD through the skin is extremely slow and appears to be a first-order process.     

Modulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated myelotoxicity by thyroid hormones

Although binding by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor is a prerequisite for toxicity, the events responsible for subsequent TCDD effects are essentially unknown. Several lines of evidence have indicated that thyroid hormones share common molecular properties with TCDD and can modulate its toxicity. In the present studies we employed suppression of murine bone marrow hematopoiesis by TCDD as an in vitro model to study the relationship between thyroid hormones and TCDD toxicity. Supraphysiological levels of thyroid hormone mimicked TCDD myelotoxicity, in that both were inhibited by a common antagonist, 1-NH2-3,7,8-trichlorodibenzo-p-dioxin. Furthermore, myelotoxicity by both TCDD and thyroid hormone segregated with the Ah locus in congenic mice. These data provide evidence of a relationship between TCDD and thyroid hormones in that hormonal activity may help regulate TCDD toxicity.     

Corticosterone decreases toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hypophysectomized rats

Male Sprague-Dawley rats were hypophysectomized by an established surgical technique. Hypophysectomy aggravated the toxicity (mortality and mean time to death) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 125 micrograms/kg ip) when compared to sham-operated rats (100% mortality with 9 +/- 1 d mean time to death vs. 90% mortality with 32 +/- 6 d mean time to death, respectively). However, administration of corticosterone (25 micrograms/ml in drinking water) to hypophysectomized rats resulted in an attenuation of the toxicity (40-60% mortality with 40-90 d mean time to death) to a range of TCDD doses (125, 250, 500 micrograms/kg) much higher than the LD50 (about 60 micrograms/kg TCDD) in nonhypophysectomized rats (about 30 d mean time to death). Furthermore, thyroid hormone supplementation in hypophysectomized rats dosed with 125 micrograms/kg TCDD restored the toxicity of TCDD to approximately "normal." Based on these data it is concluded that one or more as yet unknown key factors that are important in the modulation of the toxicity of TCDD reside in the pituitary.     

Elevation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) polychlorinated biphenyls. Structure-activity relationships

Administration of the commercial polychlorinated biphenyl (PCB) Aroclor 1254 to immature male Wistar rats resulted in increased levels (80-110%) of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) hepatic cytosolic receptor protein which remained elevated for 14 days. The effects of structure on the activity of individual PCB congeners to modulate hepatic cytosolic receptor levels were compared to the structure-activity relationships (SARs) which have been developed previously for PCBs as inducers of hepatic microsomal monooxygenases. 3,3',4,4'-Tetra- and 3,3',4,4',5-pentachlorobiphenyl induced the cytochrome P-448-dependent monooxygenase, ethoxyresorufin O-deethylase (EROD), and resembled 3-methylcholanthrene in their mode of monooxygenase enzyme induction. These congeners also bound to the receptor protein; however, neither compound increased hepatic cytosolic receptor protein levels. Several PCB congeners which exhibit low binding affinities for the cytosolic receptor protein resembled phenobarbitone (PB) in their mode of monooxygenase enzyme induction and, like PB, elevated cytosolic receptor protein levels. Nevertheless, a comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by 2,2',4,4',5,5'-hexachlorobiphenyl and PB illustrated significant differences in their activities. PB-mediated elevation of receptor levels was maximized 24 hr after the last dose, and 48 hr later the receptor levels decreased to control values. In contrast, 5 days after administration of a single dose of 2,2',4,4',5,5'-hexachlorobiphenyl (300 mumoles/kg) the receptor levels were elevated significantly, and these increased levels (205-127% increases over control) persisted for 14 days. There was no correlation between increased levels of hepatic receptor protein and the induction of the cytochrome P-450-dependent monooxygenases, aldrin epoxidase or 4-dimethylaminoantipyrine N-demethylase. Two PCBs, 2,3,3',4,4',5- and 2,2',3,4,4',5-hexachlorobiphenyl, which resembled Aroclor 1254 in their mode of monooxygenase enzyme induction, also elevated hepatic receptor protein levels but were less active than the PB-type inducers. Thus, the SARs developed for PCBs which elevate cytosolic receptor levels demonstrate that the most active compounds exhibit the lowest affinity for the receptor protein and do not induce EROD. In contrast, the more toxic PCB congeners which are approximate isostereomers of 2,3,7,8-TCDD both induced EROD and bound with high affinity to the receptor protein but did not increase hepatic cytosolic receptor protein levels.     

Acute myelotoxic responses in mice exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Blood cells are derived from a multitiered system of progenitor stem cells that lose their capacity for proliferation and self-renewal as they continue along pathways of differentiation. Since these hematopoietic events can be readily monitored in vivo and in vitro in the mouse, we have utilized this system to examine altered cellular differentiation associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity. Progenitor cells were suppressed following acute exposure of mice to TCDD at doses as low as 1.0 micrograms/kg body wt. In vitro studies demonstrated that myelotoxicity occurs by a direct inhibition of proliferating stem cells. Genetic studies indicated that the myelotoxic responses to TCDD, both in vivo and in vitro, segregate with the Ah locus. In addition, the in vitro myelotoxicity of various polyhalogenated aromatic hydrocarbon congeners correlated with their previously reported ability to induce hepatic microsomal enzyme activity and to bind to an intracellular receptor for TCDD. TCDD was also found to bind specifically to bone marrow cells from Ah-responsive, but not nonresponsive mice, indicating that bone marrow cells possess a specific receptor for TCDD. These data indicate that the myelotoxic response to TCDD is regulated by the Ah receptor present in the target tissue and demonstrates the utility of this system for examining the cellular and molecular events associated with the toxicity of polyhalogenated aromatic hydrocarbons, the prototype for which is TCDD.     

Histological analysis of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in zebrafish

Previous studies have demonstrated that acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by injection leads to inhibition of caudal fin regeneration in zebrafish. Since the TCDD exposure in these studies is systemic, it is possible that pathology in organs other than the fin could result in inhibition of fin regeneration. Therefore, histopathology of adult zebrafish (Danio rerio) organs was characterized following abdominal cavity injection of a TCDD dose (70ng/g). The most pronounced histopathologic changes 5 days post-injection included lipidosis and hypertrophy of liver hepatocytes and hypertrophy of gill lamellae. Effects of TCDD exposure on immunolocalization of the zebrafish aryl hydrocarbon receptor nuclear translocator (ARNT2), the heterodimer partner of the aryl hydrocarbon receptor (AHR2), and an AHR regulated gene cytochrome P450 1A (CYP1A) was also determined. ARNT2 was immunolocalized to the gastrointestinal tract, gill lamellae, kidney, ventricle of the heart, caudal fin, brain and liver of zebrafish. TCDD exposure had no measurable effect on ARNT2 abundance or localization. CYP1A was immunolocalized in TCDD exposed fish as a biomarker for cells with an activated AHR pathway. CYP1A was not detected in any tissue from vehicle exposed fish. Significant TCDD-dependent induction of CYP1A was detected in the proximal tubules of the kidney, in liver hepatocytes and in the gastrointestinal tract of TCDD exposed fish. Significant but lower TCDD-dependent CYP1A expression was evident in the gill, caudal fin and ventricle of the heart. Overall, TCDD exposure in adult zebrafish leads to histopathology similar to that reported in other fish species, and it appears unlikely that the histopathology in these organs completely explains the inhibition of fin regeneration.     

A metabolite of riboflavin binds to the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor

A cytosolic receptor to which TCDD binds with high affinity has been reported in a number of rodent tissues, but the endogenous/natural ligand is not known. However, lumichrome, a metabolite of riboflavin, competed with 3H-TCDD for binding to the cytosolic receptor. Neither riboflavin nor riboflavin-5-phosphate competed for binding to the TCDD receptor in rat liver cytosol. Lumichrome is the first known endogenous chemical in the rat to exhibit affinity for the TCDD receptor.     

Mode of metabolism is altered in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats

Male Sprague-Dawley rats were fed either a high-fat (HF) or a high-carbohydrate (HC) diet and subsequently injected with either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (125 micrograms/kg) or vehicle (pair-fed controls). In all TCDD-treated animals, a reduction in caloric intake was evident as early as 1 day after dosage. Respiratory quotients (RQ) were determined at 5-day intervals. Their pattern for the HC-fed but not for the HF-fed TCDD-treated rats was different from that of the corresponding pair-fed controls. After an initial parallel decrease the RQ values remained low for TCDD-treated rats whereas they increased again for pair-fed controls. Serum total thyroxine (T4) was significantly lower in TCDD-treated animals and this reduction was not influenced by the composition of the diet. Serum triiodothyronine (T3) was neither altered by diet nor by TCDD. Thymic atrophy was as severe in pair-fed as in TCDD-treated rats fed the HC diet but not in rats fed the HF diet. Our results suggest that TCDD-treated rats are in a different mode of metabolism from pair-fed rats and that this difference is related to gluconeogenesis.     

Effect of thyroidectomy and thyroxine on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced toxicity

Chemical thyroidectomy effectively protected athyroid rats from mortality during 45 days after dosing with 100 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg, whereas 70 to 80% of nonthyroidectomized-euthyroid and thyroidectomized-T4 (thyroxine)-maintained-euthyroid rats died within the same period of time. There was a significant decrease in body weight of all TCDD-treated groups compared to vehicle controls. However, body weight loss was much slower in thyroidectomized-athyroid (congruent to 1 g/day) than in nonthyroidectomized-euthyroid or in thyroidectomized-T4-euthyroid (congruent to 8 g/day) rats. TCDD significantly reduced feed intake in nonthyroidectomized-euthyroid and thyroidectomized-T4-euthyroid rats, but no altered feed consumption was observable in thyroidectomized-athyroid animals. These data indicate that thyroid hormone(s) play(s) an important role in mediating the toxicity of TCDD.     

Proliferation of periodontal squamous epithelium in mink fed 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

The maxilla and mandible from 2 adult female mink fed 5.0 ppb 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 6 mo were grossly unremarkable, but histologically had nests of squamous epithelium within the periodontal ligament. There was osteolysis of the adjacent alveolar bone.