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| Author(s): |
Ana Paula Alves Favareto
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia |
| Defense date: | 2011-03-25 |
| Examining board members: |
Wilma De Grava Kempinas;
Mary Anne Heidi Dolder;
João Lauro Viana de Camargo;
Sandra Maria Miraglia;
Glaura Scantamburlo Alves Fernandes
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| Advisor: | Wilma De Grava Kempinas |
| Abstract | |
Cisplatin is one of the most widely used and effective chemotherapeutic agents to treat several human malignancies. Nevertheless, its use is often hampered by the onset of serious side effects, especially on reproduction. Despite the widespread use of cisplatin for treatment of testicular cancer, which affects mainly young men, no reports were found about late reproductive effects caused by treatment during peri-puberty. This chemotherapeutic cause cross-links with sperm DNA, which may affect progeny of cancer survivors. Thus, the goals of the present study were to evaluate effects of the cisplatin administration during peri-puberty on several reproductive endpoints and the reversibility of these effects in adulthood. Moreover, implications of paternal treatment with cisplatin on progeny outcome, including reproduction of the adult male offspring, were evaluated. Peri-pubertal Wistar male rats (45 days old) were distributed into 2 groups. Control and Cisplatin (CP: 1mg/kg/day, 5 consecutive days/week, for 3 weeks, ip.). The study was conducted in two steps and evaluations were performed at ages of 66 (post-pubertal age, short-term evaluation) and 140 (adult age, long-term evaluation) days on: 1) organ weights, serum gonadotropins and testosterone levels, sperm counts, motility and morphology, testicular histo-morphometry, spermatogenesis kinetics, Sertoli cell number and apoptosis of germ cells. 2) sexual behavior, fertility and intratesticular testosterone were evaluated in the treated male and fetal development, postnatal growth and sexual development in its male and female progeny. In addition, fertility and other reproductive endpoints were examined in adult male offspring. At the end of CP-therapy, rats showed reductions in sperm production and reserves, sperm with progressive movement, tubular diameter, intratesticular testosterone and fertility potential, but increased numbers of TUNEL-positive seminiferous tubules, immotile sperm and pre-implantation losses compared to control. Furthermore, CP-treated post-pubertal rats displayed impaired testicular histology and sexual behavior. Serum gonadotropins and testosterone levels, sperm morphology, spermatogenesis kinetics and Sertoli cell number were comparable between experimental groups at both ages. No adverse effects in fetal development and puberty onset were seen in the offspring from CP-treated group. However, testicular descent was delayed and postnatal growth was impaired in these animals at short-term evaluation. Moreover, seminal vesicle weight, epididymal sperm count and testicular histology from adult progeny were affected by paternal exposure to cisplatin at short-term evaluation. In progeny, spermatogenesis was the unique parameter changed at long-term evaluation. Alterations found in post-pubertal CP-treated male were recovered at adulthood, except for sperm motility and damage to testicular histology. The persistence of these cisplatin effects, despite the unaltered fertility after natural mating in rats, may have implications for reproductive function of young men undergoing cancer-therapy, given the lower reproductive efficiency in humans compared to rats. Additionally, results suggest that effects of cisplatin administration during peri-puberty may be heritably transmitted and affect adversely the progeny even in a future paternity at adulthood (AU) | |