An enhanced postnatal autoimmune profile in 24 week-old C57BL/6 mice developmentally exposed to TCDD.
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 microg/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(+)CD8(+) thymocytes, and increased CD4(+)CD8(-) thymocytes, were present in the female but not male offspring. Males but not females showed decreased CD4(-)CD8(+) T cells, and increased Vbeta3(+) and Vbeta17a(+) T cells, in the spleen. Males but not females also showed increased percentages of bone marrow CD24(-)B220(+) 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 microg/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.
Mustafa
A
A
Center for Molecular Medicine and Infectious Diseases, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0342, USA.
Holladay
S D
SD
Goff
M
M
Witonsky
S G
SG
Kerr
R
R
Reilly
C M
CM
Sponenberg
D P
DP
Gogal
R M
RM
D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D017153:Antibodies, Anticardiolipin / Q000097:blood; D000974:Antibodies, Antinuclear / Q000097:blood; D000917:Antibody Formation / Q000187:drug effects; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins; D001835:Body Weight / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003176:Complement C3 / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005865:Gestational Age; D007111:Immunity, Cellular / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists; D012737:Sex Factors; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects / Q000276:immunology
D017153:Antibodies, Anticardiolipin; D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D051792:Basic Helix-Loop-Helix Proteins; D003176:Complement C3; D016207:Cytokines; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse