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Title: An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD

Abstract

Developmental exposure of mice to the environmental contaminant and AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes persistent postnatal suppression of T cell-mediated immune responses. The extent to which prenatal TCDD may induce or exacerbate postnatal autoimmune disease remains unknown. In the present study, time-pregnant high affinity AhR C57BL/6 mice received a single oral administration of 0, 2.5, or 5 {mu}g/kg TCDD on gestation day (gd) 12. Offspring of these mice (n = 5/gender/treatment) were evaluated at 24 weeks-of-age and showed considerable immune dysregulation that was often gender-specific. Decreased thymic weight and percentages of CD4{sup +}CD8{sup +} thymocytes, and increased CD4{sup +}CD8{sup -} thymocytes, were present in the female but not male offspring. Males but not females showed decreased CD4{sup -}CD8{sup +} T cells, and increased V{beta}3{sup +} and V{beta}17a{sup +} T cells, in the spleen. Males but not females also showed increased percentages of bone marrow CD24{sup -}B220{sup +} B cell progenitors. Antibody titers to dsDNA, ssDNA and cardiolipin displayed increasing trends in both male and female mice, reaching significance for anti-dsDNA in both genders and for ssDNA in males at 5 {mu}g/kg TCDD. Immunofluorescent staining of IgG and C3 deposition in kidney glomeruli increased in both genders of prenatal TCDD-exposed mice,more » suggestive of early stages of autoimmune glomerulonephritis. Collectively, these results show that exposure to TCDD during immune system development causes persistent humoral immune dysregulation as well as altered cell-mediated responses, and induces an adult profile of changes suggestive of increased risk for autoimmune disease.« less

Authors:
; ;  [1];  [2];  [1];  [3];  [2];  [4]
  1. Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1410 Prices Fork Road, Blacksburg, VA (United States)
  2. Department of Large Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1410 Prices Fork Road, Blacksburg, VA (United States)
  3. Department of Biomedical Sciences, Virginia College Of Osteopathic Medicine Blacksburg, VA 24061-0442 (United States)
  4. Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, 1410 Prices Fork Road, Blacksburg, VA (United States), E-mail: rgogal@vt.edu
Publication Date:
OSTI Identifier:
21144120
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 232; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2008.04.015; PII: S0041-008X(08)00178-6; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBODIES; BONE MARROW; CARDIOLIPIN; DIOXIN; DISEASES; GLOMERULI; MICE; ORAL ADMINISTRATION; PRENATAL EXPOSURE; PROGENY; SPLEEN; THYMOCYTES

Citation Formats

Mustafa, A., Holladay, S.D., Goff, M., Witonsky, S.G., Kerr, R., Reilly, C.M., Sponenberg, D.P., and Gogal, R.M. An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD. United States: N. p., 2008. Web. doi:10.1016/j.taap.2008.04.015.
Mustafa, A., Holladay, S.D., Goff, M., Witonsky, S.G., Kerr, R., Reilly, C.M., Sponenberg, D.P., & Gogal, R.M. An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD. United States. doi:10.1016/j.taap.2008.04.015.
Mustafa, A., Holladay, S.D., Goff, M., Witonsky, S.G., Kerr, R., Reilly, C.M., Sponenberg, D.P., and Gogal, R.M. Wed . "An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD". United States. doi:10.1016/j.taap.2008.04.015.
@article{osti_21144120,
title = {An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD},
author = {Mustafa, A. and Holladay, S.D. and Goff, M. and Witonsky, S.G. and Kerr, R. and Reilly, C.M. and Sponenberg, D.P. and Gogal, R.M.},
abstractNote = {Developmental exposure of mice to the environmental contaminant and AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), causes persistent postnatal suppression of T cell-mediated immune responses. The extent to which prenatal TCDD may induce or exacerbate postnatal autoimmune disease remains unknown. In the present study, time-pregnant high affinity AhR C57BL/6 mice received a single oral administration of 0, 2.5, or 5 {mu}g/kg TCDD on gestation day (gd) 12. Offspring of these mice (n = 5/gender/treatment) were evaluated at 24 weeks-of-age and showed considerable immune dysregulation that was often gender-specific. Decreased thymic weight and percentages of CD4{sup +}CD8{sup +} thymocytes, and increased CD4{sup +}CD8{sup -} thymocytes, were present in the female but not male offspring. Males but not females showed decreased CD4{sup -}CD8{sup +} T cells, and increased V{beta}3{sup +} and V{beta}17a{sup +} T cells, in the spleen. Males but not females also showed increased percentages of bone marrow CD24{sup -}B220{sup +} B cell progenitors. Antibody titers to dsDNA, ssDNA and cardiolipin displayed increasing trends in both male and female mice, reaching significance for anti-dsDNA in both genders and for ssDNA in males at 5 {mu}g/kg TCDD. Immunofluorescent staining of IgG and C3 deposition in kidney glomeruli increased in both genders of prenatal TCDD-exposed mice, suggestive of early stages of autoimmune glomerulonephritis. Collectively, these results show that exposure to TCDD during immune system development causes persistent humoral immune dysregulation as well as altered cell-mediated responses, and induces an adult profile of changes suggestive of increased risk for autoimmune disease.},
doi = {10.1016/j.taap.2008.04.015},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 232,
place = {United States},
year = {Wed Oct 01 00:00:00 EDT 2008},
month = {Wed Oct 01 00:00:00 EDT 2008}
}
  • Sciatic nerves of 25-week-old genetically diabetic (C57BL/Ks (db/db)) mice and their litter-mate controls were removed, and their metabolic incorporation of (/sup 3/H)fucose and (/sup 14/C)leucine into myelin was studied in vitro. Untreated diabetic animals showed significant increases (p less than 0.05) in the fucose/leucine incorporation into myelin when compared to values found for their litter-mates. These results correlated well with previous experiments performed on alloxan or streptozotocin-diabetic rats and thus show the in vitro incubation procedure to be a good indicator of altered metabolic conditions in peripheral nerves due to diabetes mellitus. The resulting ratio increases seen in diabetic animalsmore » is at variance with the decrease in ratios found in animals undergoing typical Wallerian degeneration. These results suggest that different metabolic processes operate in untreated diabetics than in normals or in those undergoing other degenerative nerve processes.« less
  • Very low doses of ionizing radiation can enhance immune responsiveness and extend life span in normal mice. Total lymphoid irradiation at relatively high doses of radiation can retard autoimmune disease in genetically susceptible mice, but may impair immune function. In order to determine whether fractionated low dose exposure would enhance immune response and retard lymphadenopathy in autoimmune-prone mice, groups of C57B1/6 lpr/lpr mice were sham irradiated, exposed 5 days/week for 4 weeks to 0.04 Gy/day, or to 0.1 Gy/day. After the radiation protocol, the mice were evaluated for splenic T cell proliferative capacity, T cell subset distribution, and total spleenmore » cell numbers. The independent and additive effect of caloric restriction was additionally assessed since this intervention has been shown to increase immune responsiveness and retard disease progression in autoimmune-prone mice. The congenic C57B1/6 +/+ immunologically normal strain was evaluated in parallel as congenic control. The results indicated that mitogen-stimulated proliferation was up-regulated in both strains of mice after exposure to 0.04 Gy/day. The proliferative capacity was additively enhanced when radiation at this dose level was combined with caloric restriction. Exposure to 0.1 Gy/day resulted in further augmentation of proliferative response in the lpr/lpr mice, but was depressive in the +/+ mice. Although the proportions of the various T cell subpopulations were altered in both strains after exposure to LDR, the specific subset alterations were different within each strain. Additional experiments were subsequently performed to assess whether the thymus is required for LDR-induced immune potentiation. Thymectomy completely abrogated the LDR effect in the +/+ mice, suggesting that thymic processing and/or trafficking is adaptively altered with LDR in this strain.« less
  • Previous studies have shown that the generation of cytotoxic T lymphocytes (CTL) following allogeneic tumor challenge is suppressed in Ah-responsive C57Bl/6 mice treated with a single oral dose of the toxic, Ah receptor-binding 3,4,5,3',4',5'-hexachlorobiphenyl (HxCB). The present studies have examined the specific role of the Ah receptor in this immunotoxic response by utilizing HxCB isomers of known, varied affinity for the Ah receptor as well as by comparing effects of high-affinity Ah receptor ligands (3,4,5,3',4',5'-HxCB and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) on the CTL response of mice that differ only at the Ah locus, that is, Ah-responsive (Ahbb) and Ah-nonresponsive (Ahdd) congenic C57Bl/6more » mice. Correlative changes in thymic weight, serum corticosterone (CS) levels, and spleen cellularity were also measured. The potency of HxCB congeners (3,4,5,3',4',5'-; 2,3,4,5,3',4'-; 2,4,5,2',4',5'-) and 2,3,7,8-TCDD to suppress the CTL response, to reduce spleen cellularity, to cause thymic atrophy, and to elevate serum CS levels was directly correlated with the binding affinity of the congener for the Ah receptor. Furthermore, these parameters of immunotoxicity in Ahdd C57Bl/6 mice were significantly more resistant to alterations induced by either 3,4,5,3',4',5'-HxCB or 2,3,7,8-TCDD as compared to Ahbb C57Bl/6 mice. These results strongly support an Ah receptor-dependent immunotoxic mechanism in suppression of the CTL response following acute exposure to halogenated aromatic hydrocarbons.« less
  • Interactions between environmental contaminants can lead to non-additive effects that may affect the toxicity and risk assessment of a mixture. Comprehensive time course and dose-response studies with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), non-dioxin-like 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and their mixture were performed in immature, ovariectomized C57BL/6 mice. Mice were gavaged once with 30 {mu}g/kg TCDD, 300 mg/kg PCB153, a mixture of 30 {mu}g/kg TCDD with 300 mg/kg PCB153 (MIX) or sesame oil vehicle for 4,12, 24,72 or 168 h. In the 24 h dose-response study, animals were gavaged with TCDD (0.3,1, 3, 6, 10, 15, 30, 45 {mu}g/kg), PCB153 (3,10, 30, 60, 100, 150, 300,more » 450 mg/kg), MIX (0.3 + 3, 1 + 10, 3 + 30, 6 + 60, 10 + 100, 15 + 150, 30 + 300, 45 {mu}g/kg TCDD + 450 mg/kg PCB153, respectively) or vehicle. All three treatments significantly increased relative liver weights (RLW), with MIX eliciting significantly greater increases compared to TCDD and PCB153 alone. Histologically, MIX induced hepatocellular hypertrophy, vacuolization, inflammation, hyperplasia and necrosis, a combination of TCDD and PCB153 responses. Complementary lipid analyses identified significant increases in hepatic triglycerides in MIX and TCDD samples, while PCB153 had no effect on lipids. Hepatic PCB153 levels were also significantly increased with TCDD co-treatment. Microarray analysis identified 167 TCDD, 185 PCB153 and 388 MIX unique differentially expressed genes. Statistical modeling of quantitative real-time PCR analysis of Pla2g12a, Serpinb6a, Nqo1, Srxn1, and Dysf verified non-additive expression following MIX treatment compared to TCDD and PCB153 alone. In summary, TCDD and PCB153 co-treatment elicited specific non-additive gene expression effects that are consistent with RLW increases, histopathology, and hepatic lipid accumulation. - Graphical abstract: Display Omitted Highlights: > MIX (TCDD:PCB153 at 1:10,000 ratio) exposure leads to non-additive gene expression. > MIX-induced liver weights are significantly greater relative to single chemicals. > MIX exposure leads to potentiation of hepatic PCB153 levels compared to TCDD. > MIX synergistically induces expression of Nqo1, Dysf, Pla2g12a, Serpinb6a, and Srxn1. > Non-additive gene expression supports putative non-additive phenotypic responses.« less
  • Although the structure and function of the AhR are conserved, emerging evidence suggests that downstream effects are species-specific. In this study, rat hepatic gene expression data from the DrugMatrix database (National Toxicology Program) were compared to mouse hepatic whole-genome gene expression data following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For the DrugMatrix study, male Sprague–Dawley rats were gavaged daily with 20 μg/kg TCDD for 1, 3 and 5 days, while female C57BL/6 ovariectomized mice were examined 1, 3 and 7 days after a single oral gavage of 30 μg/kg TCDD. A total of 649 rat and 1386 mouse genes (|fold change| ≥more » 1.5, P1(t) ≥ 0.99) were differentially expressed following treatment. HomoloGene identified 11,708 orthologs represented across the rat Affymetrix 230 2.0 GeneChip (12,310 total orthologs), and the mouse 4 × 44K v.1 Agilent oligonucleotide array (17,578 total orthologs). Comparative analysis found 563 and 922 orthologs differentially expressed in response to TCDD in the rat and mouse, respectively, with 70 responses associated with immune function and lipid metabolism in common to both. Moreover, QRTPCR analysis of Ceacam1, showed divergent expression (induced in rat; repressed in mouse) functionally consistent with TCDD-elicited hepatic steatosis in the mouse but not the rat. Functional analysis identified orthologs involved in nucleotide binding and acetyltransferase activity in rat, while mouse-specific responses were associated with steroid, phospholipid, fatty acid, and carbohydrate metabolism. These results provide further evidence that TCDD elicits species-specific regulation of distinct gene networks, and outlines considerations for future comparisons of publicly available microarray datasets. - Highlights: ► We performed a whole-genome comparison of TCDD-regulated genes in mice and rats. ► Previous species comparisons were extended using data from the DrugMatrix database. ► Less than 15% of TCDD-regulated orthologs were common to mice and rats. ► Considerations for the comparison of publicly available datasets are described.« less