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/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.
Hussain
Irshad
I
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401, USA.
Piepenbrink
Michael S
MS
Fitch
Kevin J
KJ
Marsh
James A
JA
Dietert
Rodney R
RR
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000187:drug effects* / Q000276:immunology*; D006433:Hemocyanins / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000209:etiology / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007958:Leukocyte Count; D008098:Litter Size / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011256:Pregnancy Outcome; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000033:anatomy & histology / Q000187:drug effects; D013950:Thymus Gland / Q000033:anatomy & histology / Q000187:drug effects
D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin