2,3,7,8-Tetrachlorodibenzo-p-dioxin Promotes Proliferation of Astrocyte Cells via the Akt/STAT3/Cyclin D1 Pathway / 生物医学与环境科学（英文）

OBJECTIVE@#The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a persistent organic pollutant, is harmful to the nervous system, but its effects on the brain are still unclear. This study aimed to investigate the effects of TCDD on astrocytes proliferation and underlying molecular mechanism.@*METHODS@#The cell proliferation was measured by EdU-based proliferation assay and PI staining by flow cytometry. Protein expression levels were detected by Western blotting. Immunofluorescence, cytoplasmic and nuclear fractions separation were used to assess the distribution of signal transducer and activator of transcription 3 (STAT3).@*RESULTS@#C6 cells treated with 10 and 50 nmol/L TCDD for 24 h showed significant promotion of the proliferation of. The exposure to TCDD resulted in the upregulation in the expression levels of phosphorylated protein kinase B (p-Akt), phosphorylated STAT3, and cyclin D1 in a dose- and time-dependent manner. The inhibition of Akt expression with LY294002 or STAT3 expression with AG490 abolished the TCDD-induced cyclin D1 upregulation and cell proliferation. Furthermore, LY294002 suppressed the activation of STAT3. Finally, TCDD promoted the translocation of STAT3 from the cytoplasm to the nucleus, and LY294002 treatment blocked this effect.@*CONCLUSION@#TCDD exposure promotes the proliferation of astrocyte cells via the Akt/STAT3/cyclin D1 pathway, leading to astrogliosis.

Beta-glucan prevents toxic effects of 2, 3, 7, 8-TCDD in terms of oxidative and histopathological damage in heart tissue of rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental contaminant which causes severe toxic effects. Despite there is some suggestion concerning with TCDD induced cardiotoxicity such as formation of free radicals, the main mechanism has not been entirely explained. Beta-glucan is known as strong antioxidant matter and can scavenge free radicals. Therefore this study aimed to investigate the protective effects of beta-glucan against TCDD induced cardiotoxicity in rats. In this study, 2-3 months of age and 190-250 g in weight 32 rats were randomly divided into four equal groups (n=8 for each group). Group 1 was control; Group 2 was TCDD group (2 µg/kg/week); group 3 was the beta-glucan group(50 mg/kg/day), and group 4 was TCDD and beta-glucan treatment group. The heart samples were taken from rats after 21 days treatment. The results were shown that Despite TCDD exposure visibly caused to increase (p ≤ 0.001) in TBARS levels, It caused a visible decline in the levels of GSH, CAT, GSH-Px, and SOD. However Beta glucan significantly increased GSH, CAT, GSH-Px, SOD levels and decreased generation of TBARS. Additionally, our histopathological observations were in agreement with the biochemical results. In conclusion, Beta-glucan treatment exhibited protective activity on TCDD induced cardiotoxicity

3-D reconstruction of tetrachlorodibenzo-p-dioxin effected palatal organ development model of fetal mouse / 实用口腔医学杂志

Objective:To study the feasibility of 3-D reconstruction model in the observation of tetrachlorodibenzo-p-dioxin(TCDD) effected palatal organ development of fetal mouse.Methods:Kunming mice treated 40 ug/kg TCDD by lavage on day 12.5 of pregnancy were used as in the experimental group,isodose corn oil treated in the control group.On day 13.5,14.5 and 15.5 of pregnancy heads of the fetal mice were taken out and fixed.Conventional paraffin serial sections of palatal organ were preparated and dyed by hematoxylin-eosin,images of the palatal organs were collected and photoshop treated,3-D reconstruction of the palatal organ was performed by 3D-DOCTOR software.Results:3-D reconstruction images showed that palatal organs moved from on both sides above the tongue and gradually closed and merged in the control group.In the experimental group,the palatal organs moved from on both sides above the tongue was later than control group,gradually closed,but not merged,formed cleft palate.Conclusion:3D-DOCTOR software reconstruction can be used for the study of the development process effected by TCDD in the pregnant mouse.

2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin induced testicular toxicity in rats and the protective effect of quercetin: Biochemical, histopathological and immunohistochemical studies.

Humans and animals are most sensitive to toxicant exposure during development. Dioxin, as an endocrine disruptor, is known to impair testicular functions and fertility. The present study was carried out to investigate the effects of quercetin on TCDD-induced toxicity in the testicular tissue of rats. Forty male albino rats were randomly divided into four groups (n = 10/group). Group I represent the control group; Group II administrated TCDD (27.5 μg/kg) via gavage for four week; Group III received quercetin (20 mg/kg bw.) Via gavage before TCDD administration; Group IV received quercetin alone (20 mg/kg bw). Biochemical markers included levels of testicular malondialdehyde formation and reduced glutathione as well as monitoring the activities of testicular superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase were studied. Also, serum hormonal profiles of luteinizing hormone and testosterone were reported. Our results show that administration of TCDD induces testicular damage concerning oxidative stress parameters, serum hormone level and sperm parameters. In addition, the microscopic structures of the testis, including histological and immunohistochemical studies were evaluated. Exposure to TCDD induces histopathological changes in rats testis including degeneration of seminiferous tubules, tubular necrosis, intratubular vacuolization, widened lumen and deshaped germ cells. Marked increase of apoptotic activity was observed. Also, our results clearly demonstrate the ameliorative potential of quercetin in dioxin induced testicular damage.

2,3,7,8-Tetrachlorodibenzo-P-Dioxin Induced Cell-Specific Drug Transporters With Acquired Cisplatin Resistance in Cisplatin Sensitive Cancer Cells

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce drug transporter genes such as the ATP-binding cassette G member 2 (ABCG2), which contributes to multidrug resistance. We investigated the effect of TCDD pretreatment on drug transporters induction from cancer cells of various origins. Cell viabilities after treatment of cisplatin were measured to evaluate acquiring cisplatin resistance by TCDD. Acquring cisplatin resistance was found only in cisplatin senstivie cancer cells including gastric SNU601, colon LS180, brain CRT-MG and lymphoma Jurkat cells which showed a significant increase in cell viability after combined treatment with TCDD and cisplatin. High increase of ABCG2 gene expression was found in SNU601 and LS180 cells with a mild increase in the expression of the ABCC3, ABCC5,and SLC29A2 genes in SNU601 cells, and of major vault protein (MVP) in LS180 cells. The AhR inhibitor kaempferol suppressed the upregulation of ABCG2 expression and reversed the TCDD-induced increase in cell viability in LS180 cells. However, in CRT-MG cells, other transporter genes including ABCC1, ABCC5, ABCA3, ABCA2, ABCB4, ABCG1, and SLC29A1 were up-regulated. These findings suggested the acquiring cisplatin resistance by TCDD associated with cancer cell-type-specific induction of drug transporters.

2,3,7,8-Tetrachlorodibenzo-P-Dioxin Induced Cell-Specific Drug Transporters With Acquired Cisplatin Resistance in Cisplatin Sensitive Cancer Cells

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce drug transporter genes such as the ATP-binding cassette G member 2 (ABCG2), which contributes to multidrug resistance. We investigated the effect of TCDD pretreatment on drug transporters induction from cancer cells of various origins. Cell viabilities after treatment of cisplatin were measured to evaluate acquiring cisplatin resistance by TCDD. Acquring cisplatin resistance was found only in cisplatin senstivie cancer cells including gastric SNU601, colon LS180, brain CRT-MG and lymphoma Jurkat cells which showed a significant increase in cell viability after combined treatment with TCDD and cisplatin. High increase of ABCG2 gene expression was found in SNU601 and LS180 cells with a mild increase in the expression of the ABCC3, ABCC5,and SLC29A2 genes in SNU601 cells, and of major vault protein (MVP) in LS180 cells. The AhR inhibitor kaempferol suppressed the upregulation of ABCG2 expression and reversed the TCDD-induced increase in cell viability in LS180 cells. However, in CRT-MG cells, other transporter genes including ABCC1, ABCC5, ABCA3, ABCA2, ABCB4, ABCG1, and SLC29A1 were up-regulated. These findings suggested the acquiring cisplatin resistance by TCDD associated with cancer cell-type-specific induction of drug transporters.

Effects of Artemisia capillaris extract on disorders of hepatic functions and lipid metabolism in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) / 한국영양학회지

This study was conducted in order to investigate the effects of Artemisia capillaris (AC) extract on disorders of hepatic functions and lipid metabolism induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an endocrine disrupter, using male rats (SD, five weeks old) for a period of three weeks. These 37 animals were divided into four groups. AC extract was added as 1.5% or 3% levels to basal diets, respectively. TCDD (40 ug/kg B.W) was administered by intraperitoneal injection into rats after a week from the beginning of the experiment. AC extract alleviated the increase of rat's relative liver weights induced by TCDD. Thymuses of all rats treated with TCDD were apparently shrunken by approximately 80%. Levels of white blood cells (WBC), red blood cells, hemoglobin, and hematocrits were significantly increased by treatment with TCDD, however, WBC tended to decrease by AC extract diets. In hepatic function, the elevation of glutamic oxalacetic transaminase activities by TCDD treatment was diminished by AC extract diets. Serum HDL-cholesterol levels were significantly elevated by AC extract diets. The apparent increase of triglyceride levels of rat livers induced by TCDD was significantly suppressed in the AC extract diet groups. Hepatic cytosolic catalase activities significantly decreased by treatment with TCDD showed a recovering trend by AC extract diets. In histochemical observation, the fat droplets and apoptosis of hepatocytes treated with TCDD were markedly alleviated by AC extract diets. These results indicated that AC could exert recovering effects on some disorders of hepatic functions, lipids metabolism, and antioxidant activities resulting from TCDD treatment.

Clinical Outcome of Veterans with Acute Coronary Syndrome Who Had Been Exposed to Agent Orange / 전남의대학술지

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the components of Agent Orange, has been reported to be a deadly poison despite its presence at extremely small doses. TCDD is reported to cause various kinds of cancers and other harmful effects on humans. However, a correlation between exposure to TCDD and acute coronary syndrome (ACS) is not yet proven. Thus, we examined the correlation between exposure to TCDD and ACS through an analysis of coronary angiograms from veterans of the Vietnam War. Two hundred fifty-one consecutive men undergoing coronary angiograms owing to ACS between April 2004 and May 2009 at Gwangju Veterans Hospital were analyzed. Included subjects were between 50 and 70 years of age. The patients were divided into two groups: 121 patients who had been exposed to TCDD (Group I) and 130 patients who had not been exposed to TCDD (Group II). Clinical and coronary angiographic findings were evaluated. Baseline clinical characteristics, inflammatory markers, and echocardiographic parameters were not significantly different between the two groups. The incidence of hypertension (71.1% vs. 60.0%, p=0.039) and hyperlipidemia (27.3% vs. 16.9%, p=0.038) was higher in Group I than in Group II. Total occlusion, stent length, stent use, and coronary lesion characteristics were not significantly different between the two groups. The rate of major adverse cardiovascular events (MACE) had no relationship with exposure to TCDD. Exposure to TCDD might not affect severity or the rate of MACE in persons with ACS.

Clinical Outcome of Veterans with Acute Coronary Syndrome Who Had Been Exposed to Agent Orange / 전남의대학술지

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the components of Agent Orange, has been reported to be a deadly poison despite its presence at extremely small doses. TCDD is reported to cause various kinds of cancers and other harmful effects on humans. However, a correlation between exposure to TCDD and acute coronary syndrome (ACS) is not yet proven. Thus, we examined the correlation between exposure to TCDD and ACS through an analysis of coronary angiograms from veterans of the Vietnam War. Two hundred fifty-one consecutive men undergoing coronary angiograms owing to ACS between April 2004 and May 2009 at Gwangju Veterans Hospital were analyzed. Included subjects were between 50 and 70 years of age. The patients were divided into two groups: 121 patients who had been exposed to TCDD (Group I) and 130 patients who had not been exposed to TCDD (Group II). Clinical and coronary angiographic findings were evaluated. Baseline clinical characteristics, inflammatory markers, and echocardiographic parameters were not significantly different between the two groups. The incidence of hypertension (71.1% vs. 60.0%, p=0.039) and hyperlipidemia (27.3% vs. 16.9%, p=0.038) was higher in Group I than in Group II. Total occlusion, stent length, stent use, and coronary lesion characteristics were not significantly different between the two groups. The rate of major adverse cardiovascular events (MACE) had no relationship with exposure to TCDD. Exposure to TCDD might not affect severity or the rate of MACE in persons with ACS.

Induction of Heat Shock Proteins and Antioxidant Enzymes in 2,3,7,8-TCDD-Induced Hepatotoxicity in Rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) is an environmental toxicant with a polyhalogenated aromatic hydrocarbon structure and is one of the most toxic man-made chemicals. Exposure to 2,3,7,8-TCDD induces reproductive toxicity, immunotoxicity, and hepatotoxicity. In this study, we evaluated how 2,3,7,8-TCDD-induced hepatotoxicity affect the expression of heat shock proteins and antioxidant enzymes using the real-time polymerase chain reaction (PCR) in rat. 2,3,7,8-TCDD increased heat shock protein (Hsp27, alpha-B-crystallin, Mortalin, Hsp105, and Hsp90s) and antioxidant enzymes (SOD-3, GST and catalase) expression after a 1 day exposure in livers of rats, whereas heat shock protein (alpha-B-crystallin, Hsp90, and GRP78) and antioxidant enzymes (SOD-1, SOD-3, catalase, GST, and GPXs) expression decreased on day 2 and then slowly recovered back to control levels on day 8. These results suggest that heat shock proteins and antioxidant enzymes were induced as protective mechanisms against 2,3,7,8-TCDD induced hepatotoxicity, and that prolonged exposure depressed their levels, which recovered to control levels due to reduced 2,3,7,8-TCDD induced hepatotoxicity.

Reproductive Development and Pulmonary CYP1A1 Levels in Mice Offspring Exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) During Lactation / 环境与健康杂志

Objective To explore the effect of lactational TCDD exposure alone on growing development and cytochrome P4501A1(CYP1A1) in mice offspring. Methods Mature Kunming mice (clean animal,No.604017) were divided to 2 treatment groups (40 and 20 ?g /kg bw TCDD),2 vehicle controls and 1 normal control. There were 3 maternal mice and 25-28 pups in each group. Maternal mice were administered TCDD by intraperitoneal injection in three times on post-parturition days 1,3,5,and the mice offspring were exposed to TCDD by maternal milk. The changes of body weight and the development of reproductive system were observed. The pups were sacrificed on postnatal days (PND) 35,and CYP1A1 expression in the lungs of mice offspring were measured by immunohistochemistry. Results The average body weight of mice offspring in 2 TCDD treatments decreased significantly from PND14 (P

Pathologic Comparative Studies on the Protective Effects by Panax Ginseng and Panax Quinquefolium for Treating 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Toxicity in Male Rats

BACKGROUND: Panax ginseng is known to decrease the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced testicular toxicity. Thus, we aimed to reveal the differences between Panax ginseng and Panax quinquefolium extract for their effects on TCDD-induced toxicity. METHODS: Forty rats were divided into four groups; the control group, the TCDD only group, the TCDD plus Panax ginseng group, and the TCDD plus Panax quinquefolium-treated groups. Ginseng extract was given orally to rats from day one to twenty-one. TCDD was intraperitoneally administered to rats at a single dose of 50 microgram/kg on the seventh day. The pathologic changes were then examined. The changes of body weight, cholesterol and GOT in the serum were also examined. RESULTS: The TCDD toxicity was prominent in the thymus, liver and testis. The thymus showed atrophy and an inverse pattern of lymphocyte density in the cortex and medulla. The liver revealed central necrosis with fatty changes. On electron microscopy, the seminiferous tubules showed destruction of the spermatogonia, clear spaces or vacuolar changes and degeneration in the Sertoli cells or germ cells. The above mentioned TCDD-induced changes were reduced in the rats that were administered with Panax ginseng, whereas Panax quinquefolium did not reduce these changes. CONCLUSION: The protective effects of Panax ginseng on the TCDD-induced toxicity were more effective than those of Panax quinquefolium.

Breakdown of Mucosal Immunity in Gut by 2,3,7,8-Tetraclorodibenzo-\it{p}-dioxin (TCDD)

Objectives: Mucosal immunity plays a pivotal role for body defense against infection and allergy. The aim of this study was to clarify the effects of 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD) on mucosal immunity in the gut. Methods: Fecal IgA level and oral tolerance induction were examined in TCDD-treated mice. Flow cytometric and histological analyses were also performed. Results: Single oral administration of low dose 2,3,7,8-TCDD resulted in a marked decrease in IgA secretion in the gut without any effects on the cellular components of gut-associated lymphoid tissues (GALT) including Peyer’s patches (PPs) and mesenteric lymph nodes (LNs). Decreased IgA secretion by TCDD was not observed in aryl hydrocarbon receptor (AhR)-deficient mice. Flow cytometric analysis revealed that IgA+ B cells in PPs and the mesenteric LNs remained unchanged in the TCDD-treated mice. An immunofluorescence study also demonstrated that a significant number of cytoplasmic IgA+ cells were present in the lamina propria of the gut in the TCDD-treated mice. Furthermore, oral tolerance induction by ovalbumin (OVA) was impaired in the TCDD-treated mice and OVA-specific T cell proliferation occurred in the peripheral lymphoid tissues including the spleen and LNs. Conclusions: These results suggest that a relatively low dose of TCDD impairs mucosal immunity in the gut and induces systemic sensitization by oral antigens.

Breakdown of mucosal immunity in gut by 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD)

<p><b>OBJECTIVES</b>Mucosal immunity plays a pivotal role for body defense against infection and allergy. The aim of this study was to clarify the effects of 2,3,7,8-tetraclorodibenzo-p-dioxin (TCDD) on mucosal immunity in the gut.</p><p><b>METHODS</b>Fecal IgA level and oral tolerance induction were examined in TCDD-treated mice. Flow cytometric and histological analyses were also performed.</p><p><b>RESULTS</b>Single oral administration of low dose 2,3,7,8-TCDD resulted in a marked decrease in IgA secretion in the gut without any effects on the cellular components of gut-associated lymphoid tissues (GALT) including Peyer's patches (PPs) and mesenteric lymph nodes (LNs). Decressed IgA secretion by TCDD was not observed in aryl hydrocarbon receptor (AhR)-deficient mice. Flow cytometric analysis revealed that IgA B cells in PPs and the mesenteric LNs remained unchanged in the TCDD-treated mice. An immunofluorescence study also demonstrated that a significant number of cytoplasmic IgA cells were present in the lamina propria of the gut in the TCDD-treated mice. Furthermore, oral tolerance induction by ovalbumin (OVA) was impaired in the TCDD-treated mice and OVA-specific T cell proliferation occurred in the peripheral lymphoid tissues including the spleen and LNs.</p><p><b>CONCLUSIONS</b>These results suggest that a relatively low dose of TCDD impairs mucosal immunity in the gut and induces systemic sensitization by oral antigens.</p>

Development of Luciferase Reporter Gene-based Cell Bioassay for the Aromatic Hydrocarbon Receptor Agonists

The aromatic hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates many of the biological and toxicological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and related chemicals. The application of recombinant reporter plasmid such as the firefly luciferase gene has proven to be a very effective method to detect these chemicals. The bioassay system, CALUX, is sensitive in directly detecting AhR-agonists from a variety of environmental and biologic materials. However, responses of the AhR-dependent bioassays are dependent on the cell types used. Thus, we developed a sensitive bioassay using the recombinant mouse hepatoma cell (Hepa1c1c7) for the determination of dioxins. The recombinant cell line was stably transfected with firefly luciferase reporter gene (pGudLuc1.1). The transfected cells showed the highest induction of luciferase activity at 4.5 hr and a decrease beyond this time point. The system showed the highest sensitivity of detection ever reported. Upon TCDD exposure cells showed 2 fold increase at 10 pM and 7 fold increase at 100 pM, respectively. The passage number after the transfection played an important role in the sensitivity. The increase of passage number tended to increase the sensitivity of the cells up to 15. The media without phenol red showed a higher induction rate than with phenol red, suggesting the preferable use of phenol red-free media for the bioassay. Since each of the assays has unique characteristics that make them suitable for some screening applications and not others, development of sensitive bioanalytical methods based on a variety of cellular systems in a key to the successful determination of dioxins. The bioassay system developed in this study will contribute to further development of successful screening the AhR agonists among the environmental mixture. In addition, the rapid and sensitive nature of this cellular system can be applied as a valuable tool to screen the dioxin-like moieties among the prodrugs at the initial stage, thereby expediting the new drug discovery.

Maternal Exposure to 2,3,7,8-Tetrachlorodibenzo-\it{p}-Dioxin and the Body Burden in Offspring of Long-Evans Rats

Objectives: In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a wide variety of developmental effects in pups at doses much lower than those causing overt toxicity in adult animals. We investigated the relationship between tissue concentrations of TCDD in dams and fetuses and developmental effects on pups. Materials and Methods: Pregnant Long-Evans rats were given TCDD at a single oral dose of 12.5, 50, 200, or 800 ng of TCDD or [3H]-TCDD/kg bw on gestation day (GD) 15. Dams were sacrificed on GD16 and GD21, and the tissue concentrations of TCDD were measured in dams and fetuses. Pups were sacrificed on postnatal day (PND) 49 and PND63 for males and PND70 for females, and the reproductive effects and tissue concentrations of TCDD were determined. Results: The sex ratio (male/female) on GD21 was significantly reduced at 50 ng TCDD/kg and at 12.5 and 50 ng TCDD/kg at birth, but not at other doses. Delayed puberty was observed in males at 200 ng TCDD/kg and in males and females at 800 ng TCDD/kg. Anogenital distance, testis weight, epididymal sperm count, sperm motility, and ejaculated sperm count were not affected. Estrous cyclicity was not different from that of the control in any treatment group. A dose-dependent decrease in weight of seminal vesicle and prostate on PND49 was observed. Prostate weight was significantly decreased at 800 ng TCDD/kg. At this dose, maternal body burden and TCDD concentration in fetuses were 290 pg TCDD/g and 52 pg TCDD/g on GD16, respectively. Reduced prostate weight is a sensitive and commonly observed endpoint so that the body burdens of dams and fetuses at the LOAEL of this endpoint could be served as the basis for establishing TDI for dioxins.

Preventive Effects of Chitosan on the Disorders of Hepatic Functions and Lipid Metabolism in Rats Treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

This study was conducted to fine out the preventive effects of chitosan and chitosan oligomer on the disorders of hepatic functions and lipid metabolism induced by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), using adult male rats (SD) for four weeks. Rats were fed chitosan (4%) or chitosan oligomer (4%) diets respectively before 3weeks of TCDD treatment (50 ug/kg BW) by intraperitoneal injection and then continually supplied these diets for one week until being sacrificed. The elevation of serum total and LDL cholesterol levels induced by TCDD treatment was significantly reduced in the rats fed chitosan diets. The increment of liver triglyceride levels caused by TCDD treatment was tended to suppress in all rats fed chitosan and chitosan oligomer diets. Fecal total lipid and cholesterol excretion were high levels in the rats fed chitosan diets. The hepatic cytosolic catalase activities significantly decreased by TCDD treatment appeared recovering trend by chitosan diets. In hepatic microsomal cytochrome p-450, NADPH cytochrome p-450 reductase, ethoxycoumarin-o-deethylase (ECOD) and benzphetamin N-demethylase (BPND), chitosan than chitosan oligomer diets apparently decreased the increasing levels by TCDD treatment. In histochemical observation, the fat droplets and apoptosis of hepatocytes by TCDD treatment were markedly alleviated by chitosan and chitosan oligomer diets. These results indicate that chitosan, more than chitosan oligomer can exert preventive effects on some disorders of hepatic functions and lipids accumulation by TCDD.

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and the body burden in offspring of long-evans rats

<p><b>OBJECTIVES</b>In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a wide variety of developmental effects in pups at doses much lower than those causing overt toxicity in adult animals. We investigated the relationship between tissue concentrations of TCDD in dams and fetuses and developmental effects on pups.</p><p><b>MATERIALS AND METHODS</b>Pregnant Long-Evans rats were given TCDD at a single oral dose of 12.5, 50, 200, or 800 ng of TCDD or [(3)H]-TCDD/kg bw on gestation day (GD) 15. Dams were sacrificed on GD16 and GD21, and the tissue concentrations of TCDD were measured in dams and fetuses. Pups were sacrificed on postnatal day (PND) 49 and PND63 for males and PND70 for females, and the reproductive effects and tissue concentrations of TCDD were determined.</p><p><b>RESULTS</b>The sex ratio (male/female) on GD21 was significantly reduced at 50 ng TCDD/kg and at 12.5 and 50 ng TCDD/kg at birth, but not at other doses. Delayed puberty was observed in males at 200 ng TCDD/kg and in males and females at 800 ng TCDD/kg. Anogenital distance, testis weight, epididymal sperm count, sperm motility, and ejaculated sperm count were not affected. Estrous cyclicity was not different from that of the control in any treatment group. A dose-dependent decrease in weight of seminal vesicle and prostate on PND49 was observed. Prostate weight was significantly decreased at 800 ng TCDD/kg. At this dose, maternal body burden and TCDD concentration in fetuses were 290 pg TCDD/g and 52 pg TCDD/g on GD16, respectively. Reduced prostate weight is a sensitive and commonly observed endpoint so that the body burdens of dams and fetuses at the LOAEL of this endpoint could be served as the basis for establishing TDI for dioxins.</p>

Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells

An environmental pollutant, tetrachloro dibenzo dioxin (TCDD) is known to illicit the cognitive disability and motor dysfunction in the developing brain. TCDD induced effects leading to neurodevelopmental and neurobehavioral deficit may have been defined, however underlying molecular mechanism and possible intracellular targets remain to be elucidated. In this study, we attempted to analyze TCDD-induced neurotoxic effects in the granule cells from cerebellum where certain cognitive abilities and motor function command are known to be excuted. [3H]PDBu, (phorbol 12,13-dibutyrate) binding assay indicated that TCDD induced a dose-dependent increase of total PKC activity and its induction was the aryl hydrocarbon receptor (AhR) dependent and N-methyl-D-aspartate receptor (NMDAR) independent. TCDD also caused the translocation of both PKC-alpha and -epsilon in a dose-dependent manner but associated with different receptors; PKC-alpha via AhR but not PKC-epsilon indicating an isozyme-specific pattern of the induction. Increase of the ROS formation was also observed in the cells treated with TCDD in a dose-dependent and an AhR-dependent manner. The treatment of the cells with the diamino dicyano-bis(2-aminophenylthio) butadiene (U0126, MEK-1/2 inhibitor), dizocilpine maleate (MK-801, non-competitive N-methyl-D-aspartate glutamate receptor antagonist) and vitamin E attenuated the TCDD-induced ROS production indicating that TCDD-induced ROS formation may be associated with activation of ERK-1/2 in the MAP kinase pathway or the NMDA receptor. TCDD also increased [Ca2+]i, which is associated with ROS formation and PKC activation in the cerebellar granule cells. It is suggested that TCDD activates the NMDA receptor, which may induce a sustained increase of [Ca2+]i in neurons followed by the ROS formation. Our findings may contribute to understanding the mechanism of TCDD-related neurotoxicity, thereby improving the health risk assessment of neurotoxic compounds in humans.

A Case of Incidental Epidermolytic Hyperkeratosis Occurring Normal Looking Skin Adjacent to Folliculitic Papules: In Veterans Who Participated in Vietnam War

On histological examination, an epidermolytic hyperkeratosis was observed adjacent to follicular papules on the back of a 53-year-old man. It has been reported that incidental epidermolytic hyperkeratosis occur either within various lesion (epidermal neoplasm, melanocytic neoplasm, scars, and inflammatory conditions) or in the normal skin adjacent to the lesion. This patient participated in the Vietnam War for 2 years, and had had contact with defoliants. He was treated for multiple peripheral neuropathies and cerebral infarcts. In keratinocytes, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; Agent Orange) contained in defoliating agents is associated with altered patterns of keratinocyte differentiation. So, as a cause of incidental epidermolytic hyperkeratosis, defoliant contact could be suspected.