Androgenic deficiency in male rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the male reproductive system were investigated. Sexually mature (290 g) Sprague-Dawley rats were given single oral doses of TCDD sufficient to cause varying degrees of hypophagia and impaired body weight gain. The largest doses decreased plasma testosterone and dihydrotestosterone concentrations by 90 and 75%, respectively, from ad libitum-fed control values, while decreasing seminal vesicle and ventral prostate weights by 68 and 48%. On Day 7, the approximate ED50 for these responses was 15 micrograms TCDD/kg, a nonlethal dose. Reductions in caput epididymis and testis weights were also observed. The androgenic deficiency was seen as early as 2 days after dosing and persisted for at least 12 days. Based on data from pair-fed control rats, only about half the decreases in accessory sex organ weights and in plasma androgen concentrations could be accounted for by TCDD-induced hypophagia or body weight loss. These signs of androgenic deficiency were not the result of stress (based in part on plasma corticosterone assays), nor could they be accounted for by the known effects of TCDD on steroid metabolism. While the TCDD-induced depression in plasma testosterone concentrations appears to be the primary event observed, the mechanism by which testosterone concentrations were decreased remains unknown. The androgenic deficiency may account for the male reproductive pathology and dysfunction in animals treated with overtly toxic doses of TCDD.     

Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cold-adapted rats

The toxicity of 60g/kg 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD) given IP in corn oil/5% acetone was examined in male Sprague-Dawley rats adapted to 25 °C or 4 °C ambient temperature. Cold exposure significantly reduced mean time to death and tended to increase mortality. Body weight at the time of death was reduced at both ambient temperatures to about the same extent. Thus, the rate of body weight loss was about twice as fast in nonsurvivors at 4°C than at 25 °C. There was a continuous decrease in feed intake of the non-survivors at 25 °C until death. However, no reduction in feed intake occurred in any of the rats at 4 °C ambient temperature. At 14 days after dosing all TCDD-dosed animals were hypothyroid in terms of T₄ but essentially euthyroid in terms of T₃. Oxygen consumption at 10 days after dosing was reduced to the same extent in all TCDD-dosed rats without regard to survival status. By day 20 after TCDD dosage, survivors increased their oxygen consumption at both ambient temperatures to nearly control levels whereas non-survivors were unable to do so. Body temperature of all animals remained within normal range except for the non-survivors, which showed reduced rectal temperature shortly before death. It is concluded (1) that cold adaptation aggravates the toxicity of TCDD, (2) that reduced feed intake alone cannot explain TCDD-induced wasting syndrome, (3) that reduced oxygen consumption in TCDD-treated rats may be due to reduced feed intake and/or altered thyroid hormone status, and (4) that TCDD is likely to activate metabolic pathways which represent a wasteful utilization of ingested and/or stored energy.     

Composition of diet modifies toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in cold-adapted rats

The effect of a high carbohydrate, high fat or high protein diet was studied on the acute toxicity of TCDD (125 g/kg) in cold-adapted (4±1° C) rats. Within 10 days after dosing, TCDD-treated rats fed a high carbohydrate or a high protein diet reduced their caloric intake by 25% whereas those fed a high fat diet consumed only 15% fewer kcal/MBS (metabolic body size). TCDD-treated rats fed a high protein diet lost body weight at the same rate as their pair-fed controls, whereas body weight loss in high fat-fed rats was significantly higher than in their pairfed controls. In contrast, TCDD-treated rats fed a high carbohydrate diet effectively maintained their body weight in the 4 days immediately after TCDD dosage, whereas their pair-fed controls lost weight. Mortality in TCDD-treated animals was 100% irrespective of the diet; all pairfed control rats (except one fed a high protein diet) were terminated on days corresponding to the spontaneous death of their TCDD-treated pairs. Mean time to 50% mortality and mean time to death were significantly longer in TCDD-treated rats fed a high carbohydrate diet in comparison with the other two TCDD-treated groups (p<0.05), although caloric intake was comparable. Serum triiodothyronine (T₃) was reduced in TCDD-treated animals fed a high fat or a high carbohydrate diet but not in those fed a high protein diet; serum thyroxine (T₄) was reduced in all the treated groups, irrespective of diet. The relative weight of liver was significantly higher in all TCDD-treated animals; the weight of pancreas was higher only in high carbohydrate-fed TCDD-treated rats and the weight of interscapular brown adipose tissue was lower only in high fat-fed TCDD-treated rats in comparison to pair-fed controls. It is concluded that TCDD-treated cold-adapted rats utilize carbohydrate and fat differently than pair-fed controls and that these changes probably contribute to the development of a wasting syndrome.This work was supported in part by a grant from the Bayerisches Staatsministerium für Landesentwicklung und Umweltfragen, München (Fed. Republic of Germany)     

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.     

Thyroid status and thermogenesis in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Several key aspects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity resemble the effects of hypothyroidism, while in other ways the toxic responses are characteristics of hyperthyroidism. Whether thyroid dysfunction plays a role in TCDD toxicity remained unknown, however. We therefore determined the dose-related effects of TCDD treatment on plasma concentrations of L-thyroxine (T4), 3,5,3'-triiodo-L-thyronine (T3), and thyroid-stimulating hormone (TSH), and compared these changes with signs of TCDD toxicity. We also determined whether indices of functional thyroid status (and thermogenesis) were altered in response to TCDD treatment. Young adult male Sprague-Dawley rats were given single oral doses of TCDD (6.25-100 micrograms/kg) and evaluated 1 week later. Toxicity, measured by decreases in feed intake and body weight, ranged from minimal to severe. Plasma concentrations of T4 were greatly reduced at all doses tested, while T3 was increased in a dose-related fashion (up to 35%). TSH was elevated but was inversely proportional to dose. Thyroid histology was unremarkable, and TCCD treatment had little effect on the ability of rats to raise serum T4, T3, and TSH concentrations in response to acute cold stress. TCDD treatment caused a slight (8%) decrease in basal metabolic rate, yet comparable decreases were seen in pair-fed control animals. Thermogenesis, as measured by O2 consumption and colonic temperatures in rats exposed to various ambient temperatures, was only marginally affected. In summary, although thyroid hormone concentrations were markedly altered, rats given doses of TCDD sufficient to cause overt toxicity appeared to be essentially euthyroid. These results do not support proposals by other researchers that altered thyroid status is a major contributor to TCDD toxicity and/or a key response to TCDD exposure.     

Characterization of the wasting syndrome in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Treatment of male rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a dose-dependent decrease in body weight, feed intake, resting and total oxygen consumption, and spontaneous motor activity. In animals treated with a nonlethal dose (5 or 15 μg/kg), feed intake and oxygen consumption recover within 3 weeks post-treatment to levels appropriate for the reduced weight of the animals. Rats treated with a lethal dose (50 μg/kg) lose weight continuously after treatment and typically die at a body weight approximately half that of age-matched, control rats. The similar dose and time dependencies for reduction of feed intake and weight suggest that hypophagia is the major factor responsible for weight loss in TCDD-treated rats. To determine if this hypophagia is a primary or secondry effect of TCDD treatment, rats whose body weights were reduced by food restriction prior to treatment (25 μg/kg) were studied. When allowed to feed ad libitum immediately after treatment, these animals exhibited relative hyperphagia and weight gain demonstrating that TCDD did not impair their capacity to feed. This finding suggests that the primary effect of TCDD is not on a system that controls feed intake, but rather on one that regulates body weight. It is proposed, as a heuristic model of the wasting syndrome, that TCDD treatment lowers a “set point” for regulated body weight in the rat in a dose-dependent fashion and that hypophagia serves, as a secondary response, to reduce the animal's weight to the lower regulation level determined by the dose administered.     

Factors affecting the induction of DT-diaphorase by 2,3,7,8-tetrachlorodibenzo-p-dioxin

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a toxic contaminant in some preparations of chlorinated phenols, is a potent inducer of a number of enzymes including rat liver DT-diaphorase (EC 1.6.99.2). The present study has shown that the induction of DT-diaphorase by TCDD is prevented by prior administration of actinomycin-D. In addition, it has been shown that administration of TCDD brings about an increase in NADPH-diaphorase activity in a number of extrahepatic tissues of the rat. In contrast to the rat, the adult male guinea pig, the species most sensitive to the toxic effects of TCDD, exhibits little or no increase in DT-diaphorase activity in various tissues in response to TCDD administration. The compound 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin (OCDD) is much less toxic than TCDD. OCDD was also shown to be much less potent as an inducer of rat liver DT-diaphorase than TCDD.     

Hepatic indices of thyroid status in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

The functional thyroid status of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats is unknown. Therefore, activities of certain thyroid-responsive enzymes were examined in the livers of adult male Sprague-Dawley rats 1 week after treatment with TCDD (6.25, 25 or 100 micrograms/kg). Activity of the thyroid-responsive flavin L-glycerol-3-phosphate dehydrogenase (per mg mitochondrial protein) was decreased slightly in livers of TCDD-treated rats, while that of succinate dehydrogenase remained unchanged. In contrast, activities (per mg supernatant protein) of three thyroid-responsive NADP-dependent cytosolic enzymes, malic enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, were increased by TCDD treatment in a dose-dependent manner. Lactate dehydrogenase (activity per mg supernatant protein) was also augmented slightly 1 week after TCDD administration. Liver mass was increased by TCDD treatment in a dose-dependent manner, but DNA content per liver was similar at all doses examined. Total hepatic protein, expressed per liver or mg hepatic DNA, was increased in TCDD-treated rats when compared to their pair-fed counterparts. The decreased activity of the mitochondrial L-glycerol-3-phosphate dehydrogenase, in contrast to the increased activities of the supernatant enzymes, malic enzyme, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, is not consistent with a shift in functional thyroid status following TCDD treatment.     

Differences in acute toxicity syndromes of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin in rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most potent congener of polychlorinated dibenzo-p-dioxins. The potency of 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD) is only 10% of that of TCDD for typical aryl hydrocarbon receptor (AHR)-mediated effects. Acute lethality, macroscopic effects, and liver toxicity of TCDD and HxCDD were compared in male rats of the strain Han/Wistar (Kuopio; H/W), and of the lines A and B. The latter two rat lines originate from crossbreeding of H/W and Long-Evans (Turku/AB) rats. H/W and line A rats are highly resistant to acute toxicity of TCDD due to an altered AHR, while line B rats are moderately resistant due to H/W-type alleles of another, yet unidentified gene contributing to TCDD resistance ("gene B"). The rats received 200-10,000 microg/kg of either TCDD or HxCDD intragastrically and were monitored for 46 days. In all rats, the highest dose of HxCDD (10,000 microg/kg) reduced body weight more effectively than an identical dose of TCDD. Only HxCDD (10,000 microg/kg) caused gastrointestinal hemorrhage, pale (fatty) livers and death by day 15 in H/W and line A rats. In line B rats, HxCDD caused pronounced hepatic fatty degeneration, whereas TCDD induced hepatic accumulation of biliverdin and its derivatives. Both congeners induced sinusoidal distension in liver. In H/W and line A rats, the estimated LD(50) values were >10,000 microg/kg and 2000-10,000 microg/kg for TCDD and HxCDD, respectively; for line B rats they were 480 microg/kg and 1000-2000 microg/kg, respectively. Thus, HxCDD was more potent than TCDD in inducing acute mortality in H/W and line A rats, contrary to what is predicted by toxic equivalency factor (TEF) values. In line B, the expected rank order of potencies prevailed. These findings suggest that in addition to the canonical AHR-mediated toxic pathways, HxCDD possesses an AHR-independent mechanism of toxicity, whose main manifestations are rapid body weight loss, mortality, fatty liver and gastrointestinal hemorrhage.     

Digestible energy and efficiency of feed utilization in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Treatment of male rats (300 to 325 g) with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 15 or 50 micrograms/kg) caused dose-dependent reductions in body weight, feed and water intakes, and fecal output. Urine output, however, was not altered by TCDD. Fecal energy loss, as a percentage of daily feed energy intake (kcal/day), was similar in control and TCDD-treated rats as was the percentage of feed energy absorbed by the gastrointestinal tract, i.e., digestible energy. These findings dispel the long-standing proposal that a gross malabsorption syndrome is responsible for weight loss in TCDD-treated rats and place greater emphasis on hypophagia as the reason for weight loss. In support of a central role for hypophagia, it was found that control rats pair-fed to rats treated with a sublethal dose of TCDD (15 micrograms/kg) lost almost the same amount of weight. However, from 15 to 50 days post-treatment, the pair-fed animals consistently maintained their weight at a 10- to 15-g higher level than age-matched TCDD-treated rats. To determine why this weight difference occurs, the efficiency of feed utilization from Day 30 to 45 post-treatment in ad libitum fed control and TCDD-treated rats (15 micrograms/kg) that were maintaining different levels of body weight was compared. First, daily feed intakes of TCDD-treated and control rats were determined from Day 25 to 30 post-treatment. Second, weights of both groups were lowered by reducing feed intake in two successive 5-day periods to 50 and 10% of the respective ad libitum level. Third, on Days 40 to 45, both groups were refed their prereduction level of intake but reduced in proportion to the intervening loss in metabolic tissue mass. At each level of feed energy reduction, weight losses observed in the TCDD-treated and control rats were equivalent. Furthermore, although given only prerestriction amounts of feed that were indexed to their reduced metabolic body size (body wt kg 0.75), both TCDD-treated and control rats gained weight rapidly and at similar rates during the refeeding period. Thus, rats treated with a sublethal dose of TCDD displayed normal efficiency of feed utilization but did so at a subnormal level of weight. That is, just like control rats, TCDD-treated rats increased their efficiency of feed utilization (weight gain/feed intake) but only when their body weight was caused to fall below the lower weight maintenance level determined by the TCDD dose administered.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhibition of intestinal glucose absorption in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Male Sprague-Dawley rats were injected with either 125 micrograms 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg or vehicle (pair-fed and ad libitum-fed controls). Transfer of water, electrolytes and D-glucose as well as fats of a tracer dose of the non-metabolizable radioactive marker 3-O-methyl-D-[U-14C]glucose was studied in isolated perfused jejunal segments 1, 2, 7, and 21 d after treatment (TCDD-treated and pair-fed control rats) and after 26 d in ad libitum-fed controls. TCDD-treated rats demonstrated reduced feed consumption and loss of body weight. Active intestinal absorption of glucose was significantly inhibited 30 and 22% compared to pair-fed controls, respectively 2 and 7 d after TCDD treatment. After 21 d the inhibition (14%) was less significant. There were no differences in glucose transfer between severely starved pair-fed controls (body weights 370 +/- 26 g) and ad libitum-fed rats (body weights 512 +/- 15 g). Water absorption and transfer of sodium and calcium was not influenced by TCDD treatment. However, a significant increase of potassium transfer was observed in parallel with impaired glucose absorption. The uptake of 3-O-methylglucose into mucosal tissue was not impaired, whereas the transfer to the serosal side was significantly inhibited by 30-60% compared to pair-fed as well as ad libitum-fed animals from day 2 until the end of the experiment. These results suggest that TCDD is involved in an inhibition of glucose transport at the basolateral membrane.     

Promotion of altered hepatic foci by 2,3,7,8-tetrachlorodibenzo-p-dioxin and 17beta-estradiol in male Sprague-Dawley rats.

The determination of differences in hormonal regulation of tumor promotion-related response to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) between males and females may identify factors contributing to the female-specific hepatocarcinogenicity of TCDD in rats. In the current study, diethylnitrosamine-initiated male Sprague-Dawley rats were exposed to TCDD or corn oil vehicle in the presence and absence of 17beta-estradiol (E2), and cell proliferation and development of preneoplastic altered hepatic foci (AHF) were determined. After 30 weeks of exposure, gamma-glutamyltranspeptidase (GGT)-positive AHF and the number of placental glutathione-s-transferase (PGST)-positive AHF were significantly higher in TCDD-treated rats than in control rats. Both the number and volume fraction of GGT-positive AHF were significantly lower in rats cotreated with E2 regardless of TCDD exposure compared with corresponding non-E2-treated groups and were unaffected by TCDD. In contrast, the number of PGST-positive AHF was significantly higher in E2-treated rats in the absence of TCDD treatment. In addition, whereas E2 had no effect on the volume fraction of PGST-positive foci, the levels in rats cotreated with both E2 and TCDD were significantly higher than in controls. No differences were observed in cell proliferation between TCDD-treated and control rats, although cell proliferation was lower in rats exposed to E2 compared with placebo controls. The weaker potency of tumor promotion and lack of induction of cell replication and DNA damage in male rats likely explain the female-specific hepatocarcinogenicity of TCDD in chronic bioassays.     

Relationship of the wasting syndrome to lethality in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Young adult male Sprague-Dawley rats treated with a LD95 dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibited a progressive reduction in feed intake and body weight until death occurred 15 to 32 days post-treatment. The time course and magnitude of weight loss and lethality of pair-fed control rats were essentially identical to that of TCDD-treated rats with each pair-fed control animal dying within 3 days of its TCDD-treated partner. Body composition analysis of the dead animals revealed that the total amounts of protein, fat, water, and ash in the carcasses of TCDD-treated and pair-fed control rats were each reduced to a similar extent. The temporal pattern of daily feed intake in TCDD-treated and pair-fed control rats (3 meals/day) or (1 meal/day) did not influence the results. Studies conducted at LD25-62 doses of TCDD in male Sprague-Dawley rats of different ages--weanling (90 g), young adult (275 g), and mature (450 g)--showed that the severity of the wasting syndrome in all age groups was greatest for animals that died. Also, young adult rats treated with a LD25 dose of TCDD that died displayed the same degree of hypophagia and weight loss prior to death as rats administered a LD95 dose. Histopathology of the liver and gastrointestinal tract was compared in TCDD-treated (LD95 dose) and pair-fed control rats killed 1 day before they otherwise would have died. Hepatocytes of TCDD-treated rats were enlarged relative to those of pair-fed control rats and contained nuclei that varied in size and number. Pair-fed control rats exhibited atrophy of the liver cords due to a decrease in the cytoplasmic volume of their hepatocytes. The stomach and small intestine of TCDD-treated rats were histologically similar to those of ad libitum-fed controls. In contrast, the glandular mucosa of the stomach of pair-fed control rats was ulcerated and the intestinal mucosa was atrophied. Stomach ulcers were the source of clotted blood found throughout the gastrointestinal tract of pair-fed control rats but not that of TCDD-treated animals. These findings demonstrate that hypophagia-induced weight loss is one of perhaps several responses that contribute to the death of TCDD-treated rats. That other responses are also involved is suggested by differences between pair-fed control and TCDD-treated rats in the weight and histopathology of certain organs. In addition, gastrointestinal blood loss contributes to the death of pair-fed control rats but not TCDD-treated animals.     

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.     

Effects of epidermal growth factor receptor deficiency and 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal development in mice

Dioxins are persistent environmental contaminants that cause multiple disorders in laboratory animals, including teratogenesis. In mice, the most important teratogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are hydronephrosis and cleft palate. Aryl hydrocarbon receptor (AHR) mediates most of the TCDD-induced effects, but modulation of these effects by other factors such as epidermal growth factor receptor (EGFR) has been propounded. TCDD changes the expression of both EGF and its receptor EGFR, which may be one step in the pathway leading to cleft palate and hydronephrosis. In the present study, the importance of EGFR in TCDD-induced teratogenicity was evaluated. Heterozygous EGFR^+/−-mice were mated and pregnant females exposed to 1.5–106.0 μg/kg TCDD on gestation day (GD) 10 and killed on GD 18. The fetuses were studied for cleft palate, hydronephrosis, and open eyes. There was no marked difference among the three genotypes in sensitivity to cleft palate or hydronephrosis, but in EGFR^−/−-mice frequency of the open eye malformation decreased dose-dependently. In conclusion, EGFR signaling is not required for TCDD-induced cleft palate or hydronephrosis but TCDD appears to counteract the effect of EGFR deficiency on eye opening.     

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic and uterine estrogen receptor levels in rats

Administration of a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 20 or 80 micrograms/kg) resulted in significantly decreased hepatic and uterine estrogen receptor (ER) levels in 25-day-old female Long-Evans rats. By contrast, estradiol (5 and 15 micrograms/kg) administration increased hepatic and uterine ER levels, while a combination of 2,3,7,8-TCDD plus estradiol resulted in uterine and hepatic ER levels which were similar or lower than those observed after treatment with only 2,3,7,8-TCDD. In addition, 2,3,7,8-TCDD significantly decreased the effects of estradiol on uterine wet weight increase. Competitive binding studies showed that estradiol did not bind to the aryl hydrocarbon (Ah) receptor and that 2,3,7,8-TCDD did not bind to the ER. The effects of structure on the activity of polychlorinated dibenzo-p-dioxin congeners on their activity to down-regulate hepatic and uterine ER levels were determined by using 2,3,7,8-TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 1,3,7,8-TCDD, and 1,2,4,7,8-PeCDD. Both 2,3,7,8-TCDD and 1,2,3,7,8-PeCDD exhibit high affinities for the Ah receptor and at dose levels of 80 micrograms/kg the hepatic ER levels were decreased 42 and 41%, respectively, and uterine ER levels were decreased 53 and 49%, respectively. 1,3,7,8-TCDD and 1,2,4,7,8-PeCDD bind less avidly to the Ah receptor and at dose levels of 400 micrograms/kg these compounds decreased hepatic ER levels 36 and 40%, respectively, and uterine ER levels 21 and 24%, respectively. These results support a role for the Ah receptor in the down-regulation of uterine and hepatic ER levels in the female rat by 2,3,7,8-TCDD and this effect may be associated with the decrease in spontaneous mammary and uterine tumors observed in female rats treated with 2,3,7,8-TCDD.     

Characterization of the hyperlipidemia in guinea pigs induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin

Treatment of adult male guinea pigs with a single dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 6.2 nmol (2.0 μg)/kg body wt, induces a marked hyperlipidemia characterized by a 19-fold increase in very low density lipoproteins (VLDL) and a 4-fold increase in low-density lipoproteins (LDL) compared to pair-fed control animals. VLDL from TCDD-treated animals were similar in size and electrophoretic mobility to VLDL from pair-fed control animals, but they contained less cholesteryl ester and an altered pattern of C apoproteins on sodium dodecyl sulfate-polyacrylamide gels. LDL from TCDD-treated animals were larger than LDL from pair-fed controls and contained more phospholipid and less protein than LDL from pair-fed control animals. In addition, LDL from TCDD-treated animals contained increased amounts of apoprotein C as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. No change in the concentration or properties of serum high-density lipoproteins was observed. Serum free fatty acids, triglycerides, and cholesteryl esters from TCDD-treated animals were enriched in linoleic acid (18:2), a principal fatty acid of adipose tissue. This suggests that mobilization of adipose tissue fatty acids in TCDD-treated animals may lead to increased hepatic lipoprotein production. However, weight-paired control animals did not become hyperlipidemic. Thus, in addition to mobilizing adipose tissue fatty acids, TCDD may alter the relative rates of anabolic and/or catabolic processes controlling serum VLDL and LDL concentrations in the guinea pig.     

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the hepatic storage of retinol in rats with different dietary supplies of vitamin A (retinol)

The effect of various dietary sources of vitamin A on liver storage of retinol has been investigated in Sprague-Dawley rats treated with single oral doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD): 0, 0.1, 1.0, or 10 g · kg^–1. Each dose group consisted of 3 subgroups, each comprising 10 rats which received a diet with normal, low or high retinol content. The animals were killed 4 weeks after TCDD administration. Analyses of retinol were performed by high pressure liquid chromatography and glucurono-syltransferase activities were determined spectrophotometrically. A dose-dependent decrease in hepatic storage of retinol was evident. The high retinol diet did not fully compensate for the reduction caused by the highest TCDD-dose. Glucuronosyltransferase activity increased directly in relation to the TCDD-dose but in inverse proportion to the retinol content of the diet.

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Zusammenfassung Der Einfluß verschieden hoher Gaben von Vitamin A auf die Retinolspeicherung der Leber bei Sprague-Dawley Ratten, die unterschiedliche Dosen von 2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) erhalten haben, ist untersucht worden.Jede Dosierungsgruppe bestand aus drei Untergruppen, die jeweils eine Kost mit normalem, mit erniedrigtem und mit erhöhtem Retinolgehalt verabreicht bekamen. Vier Wochen nach der TCDD-Zufuhr wurden Retinolgehalt und Glucuronosyl-Transferase-Aktivität mit Hilfe der Hoch-druckflüssigkeitschromatographie bzw. spektrofotometrisch bestimmt. Eine dosierungsabhängige Abnahme der Retinolspeicherung in der Leber war deutlich. Die Hochretinolkost war nicht fähig, die durch die höchste TCDD-Gabe verursachte Senkung ganz auszugleichen. Die Glucuronosyl-Transferase-Aktivität wuchs linear mit der TCDD-Dosis, war aber auch umgekehrt proportional mit dem Retinolgehalt der Kost.