Effects of Isotretinoin on the Reproduction of Pubertal Male Mice and Malformations in the Offspring

Laboratório de Toxicologia do Desenvolvimento, Departamento de Biologia Geral, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina/PR.

^*Corresponding Author

M J S Salles

Departamento de Biologia Geral

Centro de Ciências Biológicas

Universidade Estadual de Londrina

Londrina/PR – CCB.Campus Universitário

Rodovia Celso Garcia Cid/Pr 445 Km 380

Caixa Postal: 10.011 - CEP: 86057-970 – Londrina, Paraná,

Brasil.

Email: salmjs00@gmail.com

Abstract

Isotretinoin is a vitamin A derivative, taken orally for the treatment of several dermatoses, including severe acne. This condition affects, principally, 80% of adolescents, males being the most affected. The objective of this study was to analyze the effects of isotretinoin on the reproductive system of pubertal males, and the possible teratogenic effect on the offspring. 1 mg/kg/day of isotretinoin was administered to pubertal male Swiss mice for 45 days, via gavage. On the 35th day the animals were placed to mate with females, after which they continued to be treated for another 10 days, and on the 46th day the male mice were euthanized. Vital and sexual organs of the males were analyzed for toxicity assessment and determination of reproductive function. On the 18th day of pregnancy the females were euthanized for evaluation of intrauterine development and the presence of congenital malformations in the offspring. The results demonstrated that the administration of isotretinoin did not promote toxicity in males, but decreased the weight of the reproductive organs, and decreased testosterone levels and the Johnsen score, including a decrease in Sertoli and Leydig cell numbers. Isotretinoin promoted alterations in the spermatic morphology of both head and tail, however, did not alter the fertility rate. Regarding the intrauterine development of the offspring, there was no impairment of fetal growth; however, the drug led to decreased fetal viability, increased resorption rate, and post implantation loss, added to which skeletal and visceral malformations were identified. It is concluded that isotretinoin presented a potential toxic effect on the male reproductive system by inducing spermatic alterations which had repercussions in offspring malformations.

Keywords: spermatogenesis; isotretinoin; offspring; reproduction

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