TRANSGENERATIONAL IMPACT OF HIGH AND REPEATED DOSES OF IVERMECTIN: STUDIES IN PUPS’ TESTIS HISTOPATHOLOGY AT ADULT AGE

Objective: We previously observed that repeated high doses of ivermectin (IVM) affect the histology of the paternal testis. Currently, we are analyzing the possible transgenerational effects of paternal exposure to IVM on the histology of their offspring’s testes. Methods: Male rats were treated with IVM or its vehicle once a week for three weeks and mated with females without any treatment. Their male pups were evaluated by their body weight and the day of puberty. At adult age, these pups were divided into new groups and treated with saline or IVM, forming the following groups: saline +saline (SAL/SAL group), saline + 1.0 mg/kg of IVM (SAL/IVM group), ivermectin +saline (IVM/ SAL), and IVM plus 1.0 mg/kg (IVM/IVM group). They were euthanized, and the testis, epididymis, prostate, and seminal vesicle were weighed. The testis morphometry and histopathology were evaluated. Results: In the IVM/ SAL group, histological analysis revealed the same histological alterations observed in animals of the paternal group that received IVM, including signs of cellular disorganization. The presence of eosinophilia with vacuoles in the interstitium and the tubular lumen was also noticeable, indicating possible edema. In the IVM/IVM group, we observed that administering an additional dose of Ivermectin to the pups resulted in a significant reduction in both the height of the reproductive epithelium and the number of Leydig cells compared to the control. Conclusions: We propose that epigenetic mechanisms at the paternal sperm level, induced by IVM treatment, could be involved in these transgenerational effects. In addition, a challenge dose of IVM exacerbates these changes.