Topiramate treatment during adolescence induces short and long-term alterations in the reproductive system of female rats.

Topiramate (TPM) is an antiepileptic drug used for treating epilepsy in children, and migraine in teenagers. In this context, preclinical studies with adult female rats observed reproductive system abnormalities following treatment with TPM. Additionally, exposure to endocrine disruptors during developmental plasticity periods, such as childhood and adolescence, may influence characteristics in the adult individual. This study evaluated whether treatment with TPM during developmental periods influences the reproductive system of female rats either immediately or in adult life. Female Wistar rats were treated with TPM (41 mg/Kg/day) by oral gavage from postnatal day (PND) 16-28, or PND 28-50, which correspond to childhood and adolescence, respectively, and euthanized either 24 h after the final administration or during adulthood. Treatment with TPM during adolescence induced short-term increase in uterus and ovary weights and reduction in endometrial stroma thickness. Adult animals treated during adolescence displayed reduced primordial ovarian follicles' numbers, and increased primary and pre-antral ovarian follicles' numbers. Treatment during childhood induced no short or long-term differences. These results indicate TPM treatment during adolescence is capable of inducing short and long-term alterations on the reproductive system of female Wistar rats.

Low doses of malathion impair ovarian, uterine, and follicular integrity by altering oxidative profile and gene expression of rats exposed during the peripubertal period.

Malathion serves as a pivotal pesticide in agriculture and the management of the Aedes aegypti mosquito. Despite its widespread use, there is a notable absence of studies elucidating the mechanisms through which malathion may affect the female reproductive system. Consequently, the objective of this investigation was to assess whether exposing juvenile female rats to low doses of malathion during the juvenile and peripubertal periods could compromise pubertal onset, estradiol levels, and the integrity of the ovaries and uterus while also examining the underlying mechanisms of damage. To achieve this, thirty juvenile female rats were subjected to either a vehicle or malathion (10 mg/kg or 50 mg/kg) between postnatal days 22 and 60, with subsequent verification of pubertal onset. Upon completion of the exposure period, blood samples were collected for estradiol assessment. The ovaries and uterus were then examined to evaluate histological integrity, oxidative stress, and the expression of genes associated with cell proliferation, antiapoptotic responses, and endocrine pathways. Although estradiol levels and pubertal onset remained unaffected, exposure to malathion compromised the integrity and morphometry of the ovaries and uterus. This was evidenced by altered oxidative profiles and changes in the expression of genes regulating the cell cycle, anti-apoptotic processes, and endocrine pathways. Our findings underscore the role of malathion in inducing cell proliferation, promoting cell survival, and causing oxidative damage to the female reproductive system in rats exposed during peripubertal periods.

Treatment with topiramate in rats during childhood causes testicular structural impairment at adulthood.

Topiramate (TOP) is a psychotropic drug prescribed for the treatment of epilepsy in children older than 2 years of age and for migraine prophylaxis in adolescents. There is evidence that TOP promotes negative effects on the reproductive system of male rats. This study aimed to evaluate the immediate and late treatment effects of TOP during childhood and adolescence on the male rat reproductive system. Two experimental groups received 41 mg/kg of TOP daily, by gavage, from postnatal day (PND) 16 to 28 (TOPc group) or from PND 28 to 50 (TOPa group). Control groups (CTRc group or CTRa group) received water daily. Half of the anim-als were evaluated 24 h after the end of treatment (PND 29 and PND 51, respectively) and the remainder were evaluated in adulthood (PND120). The following parameters were determined: anogenital distance, sperm evaluation, testis' histomorphometry and plasma testosterone concentration. At PND 120, the volume (CTRc:62.58 ± 2.13; TOPc: 54.54 ± 2.10*%, p = 0.018) and total length (CTRc: 25.48 ± 1.61; TOPc: 18.94 ± 2.41*, p = 0.035) of seminiferous tubules were decreased and the volume of interstitial tissue (CTRc:37.41 ± 2.13; TOPc: 45.45 ± 2.09*%, p = 0.018) and number of Leydig cells/testis (CTRc: 277.00 ± 36.70; TOPc: 400.20 ± 13.23*, p = 0.013) were increased in the TOPc group. The other parameters remained similar between the groups. Therefore, the present study contributes to our understanding that childhood treatment with TOP has an impact on the rat reproductive system in adulthood, suggesting that this period is more sensitive to TOP exposure than adolescence.

Malathion exposure during juvenile and peripubertal periods downregulate androgen receptor and 17-ß-HSD testicular gene expression and compromised sperm quality in rats.

Malathion is an insecticide that is used to control arboviruses and agricultural pests. Adolescents that are exposed to this insecticide are the most vulnerable as they are in the critical period of postnatal sexual development. This study aimed to evaluate whether malathion damage can affect sperm function and its respective mechanisms when adolescents are exposed during postnatal sexual development. Twenty-four male Wistar rats (PND 25) were divided into three experimental groups and treated daily for 40 d: control group (saline 0.9%), 10 mg/kg (M10 group), or 50 mg/kg (M50 group) of malathion. At PND 65, the rats were anesthetized and euthanized. Testicles were collected for the evaluation of gene expression. Sperm cells from the epididymis were used for evaluation of the oxidative profile or spermatic function. Data showed that a lower dose of malathion downregulated the gene expression of androgen receptors and testosterone converter enzyme 17-ß-HSD in the testis. The acrosomal integrity of sperm cells was compromised in the M50 group, but not the M10 group. The mitochondrial activity was not impaired by exposure. Finally, although no alterations in malondialdehyde and glutathione levels were observed, malathion, at both doses, increased antioxidant enzyme catalase activity and, at a higher dose, superoxide dismutase activity. The present study showed that low doses of malathion considered to be inoffensive are capable of impairing sperm quality and function through the downregulation of testicular genic expression of AR enzyme 17-ß-HSD and can damage the spermatic antioxidant profile during critical periods of development.

Voluntary Exercise Attenuates Hyperhomocysteinemia, But Does not Protect Against Hyperhomocysteinemia-Induced Testicular and Epididymal Disturbances.

The hyperhomocysteinemia (HHcy) is toxic to the cells and associated with several diseases. Clinical studies have shown changes in plasma concentrations of Hcy after physical exercise. This study aimed to assess the effect of HHcy on testis, epididymis and sperm quality and to investigate whether voluntary exercise training protects this system against damage caused by HHcy in Swiss mice. In this study, 48 mice were randomly distributed in the control, HHcy, physical exercise, and HHcy combined with physical exercise groups. HHcy was induced by daily administration of dl-homocysteine thiolactone via gavage throughout the experimental period. Physical exercise was performed through voluntary running on the exercise wheels. The plasma concentrations of homocysteine (Hcy) and testosterone were determined. The testes and epididymis were used to assess the sperm count, histopathology, lipoperoxidation, cytokine levels, testicular cholesterol, myeloperoxidase, and catalase activity. Spermatozoa were analyzed for morphology, acrosome integrity, mitochondrial activity, and motility. In the testes, HHcy increased the number of abnormal seminiferous tubules, reduced the tubular diameter and the height of the germinal epithelium. In the epididymis, there was tissue remodeling in the head region. Ultimately, voluntary physical exercise training reduced plasma Hcy concentration but did not attenuate HHcy-induced testicular and epididymal disturbances.