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Reproductive development of male offspring obtained from female carbamazepine-treated rats, in different periods of pregnancy

Grant number: 10/06698-1
Support type:Regular Research Grants
Duration: December 01, 2010 - November 30, 2012
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Sandra Maria Miraglia Valdeolivas
Grantee:Sandra Maria Miraglia Valdeolivas
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Assoc. researchers:Samara Urban de Oliva ; Taiza Stumpp Teixeira

Abstract

Carbamazepine (CBZ) is a widely utilized drug in the control of seizure and affective disturbs as well as in the treatment of trigeminal neuralgia. It presents inhibitory effect of the testicular steroidogenesis and can cause alterations of bioactive testosterone plasmatic levels. Thus, mechanisms that depend on the adequate level of testicular testosterone can be altered by the administration of this drug even after birth. In this case, the development and maintenance of spermatogenesis in the post-natal phase are directly or indirectly dependent on the testosterone plasmatic level. Therefore, functional alterations of Leydig cells during the intrauterine phase can provoke testicular damage as well as injury of genital ducts and accessory glands; these modifications will probably be noted only postnataly, i.e., in the puberty and adulthood. CBZ is also teratogenic and causes congenital malformations of the urogenital apparatus; besides, it provokes hypothyroidism in patients that have chronically taken it. Regarding this subject, the role of the thyroid hormones (T3 and T4) on the control of the proliferation and differentiation of Sertoli cells must be considered, both in pre-natal and post-natal phases, since these cells exert a fundamental function on the establishment and homeostasis of the seminiferous epithelium microenvironment. Sertoli cells also control the differentiation and proliferation of germ cells. Moreover, during the embryonic phase, the interaction between Sertoli cells and gonocytes is crucial and has an important influence upon the normal development of male gonad, in both pubertal and adult phases. Considering the aforementioned fact, there is also the clinical aspect, since CBZ is uninterruptedly utilized by fertile women that need it. Data related to the possible side effects of CBZ exposition during pregnancy to male offspring reproduction are scarce and fragmented; in addition, in the literature consulted, there are very few studies about this subject. For that reason and because the clinical protocols including the continuous use of CBZ by pregnant patients or by women with potential reproductive capacity, we decided to carry out this experimental study with the aim to clarify the late effects of CBZ on spermatogenesis and sexual maturity of the offspring from rats treated during pregnancy. Previous study performed by our group showed that carbamazepine provokes late reproductive alterations in rats from the weaning (23 days) until the puberty and adult phase Thus we intend to perform a spermatic evaluation and to investigate the morphological, morphometric and stereological alterations of the urogenital apparatus (testes, epididymis and accessory glands) of neonate, pubertal and adult rats whose mothers were CBZ- treated during different and critical gestational phases of the male genital system formation. The study will emphasize the testicular alterations. (AU)