Developmental immunotoxicity of cyclosporin-A in rats: age-associated differential effects

Cyclosporin-A (CYP-A) is a widely used immunosuppressive drug. Yet, information on the long-term impact of embryonic exposure is relatively scarce. The effects of CYP-A on reproductive and immunologic parameters in CD strain female offspring exposed in utero at doses of 0, 0.2, 2, 10, or 20 mg/kg/da...

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Published in:	Toxicology (Amsterdam) Vol. 206; no. 2; pp. 273 - 284
Main Authors:	Hussain, Irshad, Piepenbrink, Michael S., Fitch, Kevin J., Marsh, James A., Dietert, Rodney R.
Format:	Journal Article
Language:	English
Published:	Shannon Elsevier Ireland Ltd 15-01-2005 Amsterdam Elsevier Science
Subjects:	Animals Animals, Newborn Anti-KLH Ig-E Anti-KLH Ig-G Biological and medical sciences Body Weight - drug effects Cyclosporin-A Cyclosporine - toxicity Cytokines Cytokines - immunology Cytokines - metabolism Delayed type hypersensitivity Female Fetal Development - drug effects Fetal Development - immunology Hemocyanins - immunology Hypersensitivity, Delayed - etiology Hypersensitivity, Delayed - immunology Immunoglobulin G - blood Immunosuppressive Agents - toxicity Leukocyte Count Litter Size - drug effects Medical sciences Nitric Oxide - biosynthesis Organ Size - drug effects Pregnancy Pregnancy Outcome Random Allocation Rats Rats, Sprague-Dawley Spleen - anatomy & histology Spleen - drug effects Splenocytes T-cells Thymus Gland - anatomy & histology Thymus Gland - drug effects Toxicology T-cells Delayed type hypersensitivity Cyclosporin-A Cytokines Splenocytes Anti-KLH Ig-G Anti-KLH Ig-E Allergy Immunopathology Immunoglobulins Rat Toxicity Rodentia Cytokine Delayed hypersensitivity Splenocyte Vertebrata Mammalia Animal T-Lymphocyte Development Ciclosporin Immunosuppressive agent Age
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Summary:	Cyclosporin-A (CYP-A) is a widely used immunosuppressive drug. Yet, information on the long-term impact of embryonic exposure is relatively scarce. The effects of CYP-A on reproductive and immunologic parameters in CD strain female offspring exposed in utero at doses of 0, 0.2, 2, 10, or 20 mg/kg/day (from gestational day 6 to 21) were compared against identically dosed CD adult rats. Embryotoxicity was seen at the two highest doses. CYP-A was acutely immunotoxic in adults (tested at 20 mg/kg/day dose) but with minimum long-term effects. In contrast, the offspring experienced relatively persistent alterations. CYP-A exposure increased ano-genital distance in the neonates. In the 5-week-old offspring, the delayed type hypersensitivity (DTH) response and splenic B cell number (determined by flow cytometry) were both decreased at the 2 mg dose level. IL-4 level was reduced and blood monocytes were increased at both exposure doses. All other parameters were unchanged. In the adult offspring (13-week-old), no difference was seen in either the DTH response or B cell ratios, but IL-4 level was increased at 2 mg/kg/day, and anti-KLH IgG titer decreased at both doses. In exposed non-pregnant adults, changes were minimal following a 13-week recovery period. Blood neutrophils were increased at all doses of the drug and flow cytometry data suggested some perturbation in CD4 +CD8 + cells, macrophages, and B-cells. All other parameters were unchanged. In conclusion, the adult rodent immune system largely recovers from CYP-A exposure given sufficient time. However, embryonic exposure appears to produce a series of immune perturbations including functional impairment during postnatal maturation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0300-483X 1879-3185
DOI:	10.1016/j.tox.2004.08.019