Can exposure to lisdexamfetamine dimesylate from juvenile period to peripubertal compromise male reproductive parameters in adult rats?

Lisdexamfetamine (LDX) is a d-amphetamine prodrug used to treat attention deficit and hyperactivity disorder, a common neurodevelopmental disorder in children and adolescents. Due to its action mediated by elevated levels of catecholamines, mainly dopamine and noradrenaline, which influence hormonal regulation and directly affect the gonads, this drug may potentially disrupt reproductive performance. This study evaluated the effects of exposure to LDX from the juvenile to peripubertal period (critical stages of development) on systemic and reproductive toxicity parameters in male rats. Male Wistar rats (23 days old) were treated with 0; 5.2; 8.6 or 12.1 mg/kg/day of LDX from post-natal day (PND) 23 to 53, by gavage. LDX treatment led to reduced daily food and water consumption, as well as a decrease in social behaviors. The day of preputial separation remained unaltered, although the treated animals exhibited reduced weight. At PND 54, the treated animals presented signs of systemic toxicity, evidenced by a reduction in body weight gain, increase in the relative weight of the liver, spleen, and seminal gland, reduction in erythrocyte and leukocyte counts, reduced total protein levels, and disruptions in oxidative parameters. In adulthood, there was an increase in immobile sperm, reduced sperm count, morphometric changes in the testis, and altered oxidative parameters, without compromising male sexual behavior and fertility. These findings showed that LDX-treatment during the juvenile and peripubertal periods induced immediate systemic toxicity and adversely influenced reproductive function in adult life, indicating that caution is necessary when prescribing this drug during the peripubertal phase.

Safety evaluation of ondansetron after gestational exposure on male reproductive parameters in rats.

Ondansetron is a 5HT3 receptor antagonist widely used to treat hyperemesis gravidarum, although its safety is still questionable. Since 5HT3 receptors, which are the target of this drug, can interfere with brain development through changes in neurotransmitter levels, this study evaluated whether the prenatal exposure to this drug could compromise reproductive and behavioral parameters in male offspring. Pregnant rats were treated with ondansetron (1.7 and 2.5 mg/kg/body weight; gavage), from gestational day 1-21. No exposure-related changes in clinical signs, body weight, food consumption, pregnancy length, and necropsy findings were observed in dams. Ondansetron exposure did not alter the anogenital distance or age of preputial separation in male offspring. Similarly, males exposed to therapeutic doses of ondansetron did not exhibit changes in play behavior. In adulthood, there were no changes in sperm parameters, as well as in testosterone level, sexual behavior and fertility. Furthermore, ondansetron did not interfere with testicular and epididymal histology, and with androgen receptor expression in hypothalamus. In conclusion, prenatal exposure to ondansetron did not cause maternal toxicity, as well as did not interfere with reproductive parameters of male offspring, indicating its safety after gestational exposure in rats.

Long-term reproductive effects of benzo(a)pyrene at environmentally relevant dose on juvenile female rats.

Since studies on the reproductive consequences after the exposure to environmentally relevant doses of Benzo(a)pyrene (BaP) during critical stages of development are scarce, this study evaluated female reproductive parameters of adult rats exposed to a low dose of BaP during the juvenile phase. Female rats (Post-natal 21) were treated with BaP (0 or 0.1 µg/kg/day; gavage) for 21 consecutive days. During the treatment, no clinical signs of toxicity were observed. Nevertheless, the ages of vaginal opening and first estrus were anticipated by the BaP-exposure. At the sexual maturity, the juvenile exposure compromised the sexual behavior, as well as the placental efficiency, follicle stimulating hormone levels, placenta histological analysis, and ovarian follicle count. A decrease in erythrocyte, platelet, and lymphocyte counts also was observed in the exposed-females. Moreover, the dose of BaP used in this study was not able to produce estrogenic activity in vivo. These data showed that juvenile BaP-exposure, at environmentally relevant dose, compromised the female reproductive system, possibly by an endocrine deregulation; however, this requires further investigation.

Preclinical safety evaluation of the ethanolic extract from campomanesia guazumifolia (cambess.) O. Berg fruits peels in rats.

The toxicological potential of the ethanolic extract from Campomanesia guazumifolia (EECG), a species traditionally recognised for its antidiabetic, anti-inflammatory and hypercholesterolemic properties, was investigated in acute and subacute toxicity models in rats. In the acute toxicity test, 2000 mg/kg of EECG was administered orally in female rats, while male and female rats received 250, 500 or 750 mg/kg of EECG for the subacute toxicity test. No evidence of toxicity was observed in the animals acutely exposed, indicating that the LD50 is above 2000 mg/kg. However, repeated exposure to this extract resulted in alterations in important biochemical parameters indicative of hepatic and renal toxicity, including AST, ALT, creatinine, urea, and cholesterol. Additionally, some hematological parameters were also changed by the treatment. EECG demonstrated low toxicological potential. Nevertheless, given the observed changes in liver and kidney enzymes, further investigations into the protective effects of this extract following repeated administration are warranted.

Maternal-fetal safety evaluation of an aqueous extract of Casearia sylvestris leaves in rats.

BACKGROUND: This study evaluated the maternal, embryotoxic, and teratogenic effects of the aqueous extract of Casearia sylvestris (AECS), a species listed in the Unique Health System of Brazil, and widely used for treating several conditions, such as diarrhea, wounds, pain, and ulcers. METHODS: Pregnant rats were daily treated orally with 0, 175, 350, or 700 mg/kg/body weight of AECS, from gestational day (GD) 6 to 15 (organogenesis period). On GD 20, the pregnant rats were euthanized, and the litters submitted to an assessment of fetal development. RESULTS: No clinical signs of toxicity were observed in the dams during the treatment. In the embryo-fetal development study, a significant increase in the basal zone height of the placenta was observed in the intermediate dose group. Furthermore, there was a significant increase in the relative anogenital distance measurement of female fetuses in the lowest and intermediate dose groups. Although no visceral abnormalities were observed in the treated-fetuses, skeletal anomalies evidenced by changes in the ossification of the sternum and the presence of supernumerary ribs were found in the intermediate and high dose groups. CONCLUSION: In conclusion, the treatment with AECS during organogenesis at this dose level had detrimental effects on the normal development of fetuses.

Paternal low-dose benzo(a)pyrene exposure in rats impairs sexual development and fertility of the paternal lineage in F2 generation: A transgenerational study.

The field of Paternal Origins of Health and Disease (POHaD) is highly relevant but remains under-explored. The F2 generation from males indirectly exposed (F1 - via germ cells) to benzo(a)pyrene (BaP), named PF2, was investigated in this study under parameters of sexual development and reproductive performance of male and female rats. Male Wistar rats (F0) were exposed to BaP (0.1 µg/kg/day) for 31 consecutive days (gavage) during prepuberty. The F0 rats were mated with untreated females to produce male offspring (F1), which were exposed to BaP via germ cells. The F1 males were later mated with untreated females to obtain the PF2 generation, which was the focus of our investigation. Our findings showed that PF2 males exhibited a decrease in anogenital distance, fertility potential, testosterone levels, and type A sperm. Meanwhile, PF2 females had an earlier vaginal opening, lower lordosis scores, and decreased fertility. Furthermore, changes in the histomorphology of the testis/epididymis and ovary/uterus were observed. The repercussions of the PF2 generation indicate that these animals showed losses in both sexual development and fertility potential, and we can conclude that this damage remained due to paternal transgenerational inheritance caused by a low dose of BaP.