Influência da exposição in utero e lactacional ao tamoxifeno: repercussão tardia em parâmetros reprodutivos e comportamentais, em ratos machos adultos

Abstract

Tamoxifen, selective non-steroidal estrogen receptor modulator, is used as adjuvant endocrine therapy in patients with breast cancer positive for hormone receptors. Since many breast cancer patients are of reproductive age, pregnancy is postponed until the end of treatment due to the potential teratogenic effect of the drug. However, information on the risk of using tamoxifen during pregnancy is still scarce, especially if the exposure occurs during the period of sexual differentiation of the brain, which is sensitive to estradiol. Furthermore, this drug is a potential endocrine disruptor capable of interfering with reproduction in non-target organisms. Since tamoxifen has an anti-estrogenic action, the aim of this study was to evaluate the effects of maternal exposure to tamoxifen on reproductive parameters in male rats. Therefore, pregnant Wistar rats (n=32) were exposed to three doses of tamoxifen (0.12; 0.6; or 3 µg /kg), from the last week of gestation (Gestational days 15-21) to the end of lactation (Postnatal day 20), via gavage. During treatment, water and food consumption, body mass and maternal behavior of exposed rats were monitored. At the end of the treatment, blood was collected from the mothers for biochemical analyzes and organs for recording the weight. After birth, male offspring were evaluated using the following parameters: determination of body weight, anogenital distance, ages of preputial separation, testicular descent and play behavior. In adult life, these same animals were investigated regarding: reproductive organ weights, sperm count, sperm morphology and motility, histological analysis of the testis and epididymis, expression of androgen receptors in the hypothalamus, sexual behavior and sexual preference. Tamoxifen treatment did not interfere with the evaluated maternal parameters. In the assessment of the initial development of male offspring, changes in body weight and delay in the age of preputial separation (biomarker of puberty onset) were observed. In adult life, exposure to tamoxifen did not change the relative organs weight, sperm morphology, testicular histological parameters, expression of androgen receptors or fertility, although it did cause alterations in sperm motility, sperm count and histopathological alterations were found in the epididymis. However, there was no change in behavioral parameters. Therefore, maternal exposure to tamoxifen was able to affect sexual maturation and compromised the sperm quality and quantity of male offspring.