| 1. |
- Gunnarsson, David, et al.
(författare)
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Cadmium-induced decrement of the LH receptor expression and cAMP levels in the testis of rats
- 2003
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Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 183:(1-3), s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- Cadmium (Cd) is a widespread environmental pollutant, characterized by its ability to affect various organs. Adverse effect of Cd on the testis including decreased testosterone production are well-known phenomena, but the cellular events explaining these effects have not yet been established. In the present study the initial steps of gonadotropin mediated testosterone biosynthesis were examined in vivo in rats, in relation to Cd dose and time after injection. In the dose–response experiment Male Sprague–Dawley rats received a single subcutaneous (sc) injection of CdCl2 (1, 5 or 10 μmol/kg body weight) and were sacrificed 48 h after injection. A statistically significant decrease in luteinizing hormone (LH) receptor mRNA level in the testicular tissue was demonstrated at the highest dose (10 μmol/kg). In the temporal–response experiment rats were given 10 μmol/kg of CdCl2 sc and sacrificed 0.48, 4.8, 48 or 144 h after injection. LH receptor mRNA levels as well as cyclic adenosine monophosphate (cAMP) levels were found to be significantly lowered at 48 and 144 h. These observations of the mechanisms whereby Cd exerts its effect on the initial steps of testosterone biosynthesis are the first from in vivo experiments.
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| 2. |
- Lind, Monica, et al.
(författare)
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Change of bone tissue composition and impaired bone strength in rats exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126)
- 2000
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Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 150:1-3, s. 41-51
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Tidskriftsartikel (refereegranskat)abstract
- In previous studies we have described structural and functional changes in rat bone tissue caused by 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). Some of the effects caused by PCB126 resemble those found in vitamin C-deficient rats, as well as those found in rats with a high dietary intake of vitamin A. The present investigation was designed to determine if these PCB126-induced changes could be inhibited by addition of vitamin C to the drinking water and if they could be evoked by vitamin A administration. Five groups of female rats were used in this study, which lasted for 12 weeks. Three of the groups were exposed to PCB126 (total dose 320 μg/kg, bw), either alone or in combination with vitamin C added to the drinking water (1 and 10 g/l, respectively). One group was given feed with increased level of vitamin A (600 000 U/kg pellet) and the fifth group served as controls. Using peripheral quantitative computed tomography (pQCT), it was found that PCB126 increased trabecular density and cortical thickness, but reduced the trabecular area. Furthermore, maximum torque and stiffness of the humerus during torsional testing and serum osteocalcin levels were reduced by PCB126. Of the PCB126 induced effects observed, addition of vitamin C only inhibited the reduction of serum osteocalcin. Like PCB126 vitamin A supplementation increased the inorganic content and the bone density and also reduced the trabecular area and polar moment of inertia but did not increase the cortical thickness or reduce maximum torque, stiffness or serum osteocalcin level. Apparently, the effects induced by PCB126 are not mediated either via decreased vitamin C level or increased vitamin A level.
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| 3. |
- Rudén, Christina
(författare)
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Interpretations of primary carcinogenicity data in 29 trichloroethylene risk assessments
- 2001
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Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 169:3, s. 209-225
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Tidskriftsartikel (refereegranskat)abstract
- This paper explores to what extent interpretations of individual primary carcinogenicity data differ between different risk assessors, and discusses possible reasons for such differences as well as their impact on the overall risk assessment conclusions. For this purpose 29 different TCE carcinogenicity risk assessments are used as examples. It is concluded that the TCE risk assessors surprisingly often interpret and evaluate primary data differently. Two particular reasons for differences in data interpretation are discussed: different assessments of statistics, and different assessments of whether the results obtained in bioassays have toxicological relevance. Differences in the interpretation and evaluation of epidemiological data are also explored and discussed.
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| 4. |
- Gunnarsson, David, et al.
(författare)
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Pronounced induction of testicular PGF(2 alpha) and suppression of testosterone by cadmium-prevention by zinc.
- 2004
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 200:1, s. 49-58
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Tidskriftsartikel (refereegranskat)abstract
- In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F(2 alpha) (PGF(2 alpha)) production, adult male Sprague-Dawley rats were exposed to CdCl(2) by subcutaneous injections. Dose-response as well as temporal-response experiments were performed, and PGF(2 alpha) levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 micromol/kg) caused a dramatic elevation of testicular PGF(2 alpha), which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF(2 alpha) levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 micromol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF(2 alpha) synthesis (22.3-fold) detected after exposure to 20 micromol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF(2 alpha) levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF(2 alpha) but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF(2 alpha) production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.
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| 5. |
- Lind, Monica, et al.
(författare)
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Bone tissue composition, dimensions and strength in female rats given an increased dietary level of vitamin A or exposed to 3,3',4, 4',5-pentachlorobiphenyl (PCB126) alone or in combination with vitamin C.
- 2000
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Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 151:1-3, s. 11-23
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Tidskriftsartikel (refereegranskat)abstract
- In previous studies we have described structural and functional changes in rat bone tissue caused by 3,3',4,4',5-pentachlorobiphenyl (PCB126). Some of the effects caused by PCB126 resemble those found in vitamin C-deficient rats, as well as those found in rats with a high dietary intake of vitamin A. The present investigation was designed to determine if these PCB126-induced changes could be inhibited by addition of vitamin C to the drinking water and if they could be evoked by vitamin A administration. Five groups of female rats were used in this study, which lasted for 12 weeks. Three of the groups were exposed to PCB126 (total dose 320 microgram/kg, bw), either alone or in combination with vitamin C added to the drinking water (1 and 10 g/l, respectively). One group was given feed with increased level of vitamin A (600000 U/kg pellet) and the fifth group served as controls. Using peripheral quantitative computed tomography (pQCT), it was found that PCB126 increased trabecular density and cortical thickness, but reduced the trabecular area. Furthermore, maximum torque and stiffness of the humerus during torsional testing and serum osteocalcin levels were reduced by PCB126. Of the PCB126 induced effects observed, addition of vitamin C only inhibited the reduction of serum osteocalcin. Like PCB126 vitamin A supplementation increased the inorganic content and the bone density and also reduced the trabecular area and polar moment of inertia but did not increase the cortical thickness or reduce maximum torque, stiffness or serum osteocalcin level. Apparently, the effects induced by PCB126 are not mediated either via decreased vitamin C level or increased vitamin A level.
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| 6. |
- Lind, Monica, et al.
(författare)
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Estrogen supplementation modulates effects of the endocrine disrupting pollutant PCB126 in rat bone and uterus : diverging effects in ovariectomized and intact animals.
- 2004
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 199:2-3, s. 129-136
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Tidskriftsartikel (refereegranskat)abstract
- The aims of the present study are to compare effects of estrogen depletion (OVX) and estradiol (E2) supplementation on the tissue effects of exposure to the endocrine disrupting organochlorine 3,3',4,4',5-pentachlorobiphenyl (PCB126). For this purpose two highly estrogen-dependent tissues, bone and uterus, were studied. Forty rats exposed to PCB126 (ip) for 3 months (total dose 384 microg/kg body weight (bw)) were randomized in to OVX/sham operation or E2 supplementation (ip, 23 microg/kg, 3 days weekly) per vehicle (corn oil) groups in a 2 x 2 factorial design. Sham operated rats were treated with vehicle, PCB or PCB plus E2 (sham, sham + PCB and sham + PCB + E2, n=10 per group) whereas ovariectomized were treated with vehicle, PCB or PCB plus E2(OVX, OVX + PCB and OVX + PCB + E2, n=10 per group). As control groups served OVX or sham, and OVX + E2 (n=10 in each group). In OVX rats PCB126 + E2 treatment increased trabecular bone volume (TBV) (P<0.01), whilst the opposite was found in sham-operated rats (P<0.01). In OVX animals exposed to PCB126, E2 supplementation decreased the uterine weight and increased the uterine ERbeta mRNA level, whilst no difference was found between the PCB126 and PCB126 + E2 exposed groups in the sham-operated animals. In conclusion, estrogen modulates PCB126 induced effects on trabecular bone, as well as several uterine parameters. These results further support an important role of estrogen on the toxic effects of PCB126 on bone and uterus.
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| 7. |
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| 8. |
- Mellergård, Johan, et al.
(författare)
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Short- and long-term effects of T-cell modulating agents in experimental autoimmunity
- 2004
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 196:3, s. 197-209
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Tidskriftsartikel (refereegranskat)abstract
- Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2 s) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2s) mice were given 6mg HgCl2/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.
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| 9. |
- Hultberg, Björn, et al.
(författare)
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Interaction of metals and thiols in cell damage and glutathione distribution: potentiation of mercury toxicity by dithiothreitol
- 2001
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Ingår i: Toxicology. - 0300-483X. ; 156:2-3, s. 93-100
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we have investigated the effects of extracellular redox status and metal/thiol interactions on glutathione distribution in HeLa cell cultures. No effects were seen on glutathione distribution after the addition of different thiols, whereas the pro-oxidant copper ions affected glutathione distribution in several ways. The addition of dithiothreitol (DTT) but not the other thiols potentiated the effects of mercury ions on glutathione distribution and cell toxicity. In the presence of DTT, increased intra- and extracellular glutathione concentrations were noted already at 0.05 micromol/l, which was below the previously reported toxicity threshold for mercury ions in blood. Likewise DTT potentiated the effects of copper ions on glutathione distribution and cell toxicity, whereas the addition of DTT to cell cultures with a non-metal thiol reactive agent (hydroquinone) or an oxidative agent (hydrogen peroxide) did not affect glutathione distribution or cell toxicity. Thus, it seems as the synergistic effects between DTT and thiol reactive agents only apply to metal ions.
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| 10. |
- Hultberg, Björn, et al.
(författare)
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Lipoic acid increases glutathione production and enhances the effect of mercury in human cell lines.
- 2002
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Ingår i: Toxicology. - 0300-483X. ; 175:1-3, s. 103-110
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Tidskriftsartikel (refereegranskat)abstract
- Thiols are known to influence the metabolism of glutathione. In a previous study (Toxicology 156 (2001) 93) dithiothreitol (DTT) did not show any effect on intra- or extracellular glutathione concentrations in HeLa cell cultures but increased the effects of mercury ions on glutathione concentrations, whereas monothiols such as N-acetylcysteine (NAC) or glutathione did not. In the present study, we have investigated the effects of thiols as well as the interaction between thiols and mercury ions in cultures of both HeLa and hepatoma cells. Furthermore, we have added alpha-lipoic acid (LA) to the previously used test panel of thiols, since it is metabolised intracellularly to a dithiol (dihydrolipoate). The present study shows that LA increased intra- and extracellular concentrations of glutathione in both HeLa and hepatoma cell cultures. In contrast to results for HeLa cells, the presence of DTT increased the intracellular glutathione concentration in hepatoma cells. No increase of glutathione concentrations was observed in hepatoma cell cultures in the presence of the monothiols (NAC, homocysteine or glutathione) tested, in agreement with previous findings in HeLa cell cultures. The presence of dithiols, either DTT or dihydrolipoate (the metabolite of LA), increased the effects of mercury ions on glutathione concentrations in hepatoma cells, whereas monothiols such as NAC or glutathione did not, in agreement with previous findings in HeLa cells. Thus, metabolic effects of mercury ions were observed in hepatoma cells as well as in HeLa cells at a lower concentration than the supposed toxicity threshold for mercury in blood.
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