Ovarian Histological Alterations and Fetal Developmental Effects Induced by A Novel Anticancer Phosphoramidate Nucleotide in Rats

Abstract

The present study evaluated the reproductive toxicity of a novel compound, SH-PAN-19, in pregnant rats. To assess ovarian toxicity, SH-PAN-19 was administered at 25 and 100 mg/kg through a single dose, while fetal outcomes were examined following drug administration on gestational day 16. Fetal development and ovarian morphology were assessed on gestational day (GD18), with additional ovarian recovery analysis performed 21 days post-treatment. Administration of 25 mg/kg intraperitoneally caused a little yet significant reduction in fetal weight and crown–rump length, whereas 100 mg/kg via oral gavage resulted in complete fetal resorption. Histological analysis demonstrated dose-dependent ovarian damage. Control ovaries exhibited normal follicular development, whereas exposure to 25 mg/kg resulted in moderate follicular depletion and a reduced number of corpora lutea. In contrast, the 100 mg/kg dose severely disrupted folliculogenesis, leading to extensive ovarian deterioration. Recovery studies indicated that ovarian damage at 25 mg/kg was largely reversible, while exposure to 100 mg/kg produced persistent and irreversible injury. Collectively, these findings demonstrate that SH-PAN-19 induces pronounced dose-dependent embryotoxicity and ovarian toxicity, underscoring the substantial risk associated with high-dose exposure, while suggesting that the recommended 25 mg/kg dose during the third trimester may still pose potential risks to female fertility and pregnancy outcomes.