Arsenic trioxide exposure impairs testicular morphology in adult male mice and consequent fetus viability

ABSTRACT

The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As₂O₃) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As₂O₃ may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As₂O₃ was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine sub-chronic treatment effects of As₂O₃ on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As₂O₃ subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As₂O₃ (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As₂O₃-treated males. Data indicate that As₂O₃ exposure altered the spermatogenic process and subsequently fetal viability.

KEYWORDS:

• Arsenic trioxide
• sperm malformation
• post-implantation loss
• androgen receptor
• toxicology

Acknowledgments

The authors are grateful to CNPq, The São Paulo Research Foundation (FAPESP 2012/14342-8) and the Coordinator for Improvement of Higher Education Personnel (CAPES), for graduate scholarships and to José Eduardo Bozano, from the Department of Morphology of UNESP, for the excellent technical assistance. Dr. Wilma De Grava Kempinas is recipient of a senior research fellowship from CNPq (National Council for Scientific and Technological Development).

Funding

This work was supported by The São Paulo Research Foundation; [FAPESP 2012/14342-8]; Improvement of Higher Education Personnel (CAPES).

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Additional information

Funding

This work was supported by the State of São Paulo Research Foundation; [FAPESP 2012/14342-8]; Improvement of Higher Education Personnel (CAPES).