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

• Published in: Journal of Toxicology and Environmental Health, Part A Part A, 2017-01, Vol.80 (19-21), p.1166-1179
• Main Authors: da Silva, Raquel Frenedoso, Borges, Cibele dos Santos, de Almeida Lamas, Celina, Cagnon, Valéria Helena Alves, de Grava Kempinas, Wilma
• Format: Article
• Language: English
• Subjects: Acute promyeloid leukemia; androgen receptor; Androgen receptors; Animals; Apoptosis; Arsenic; Arsenic trioxide; Arsenicals - administration & dosage; Cytoplasm; Degeneration; Disease Models, Animal; Distilled water; Epididymis; Epididymis - drug effects; Epididymis - metabolism; Epithelium; Exposure; Females; Fertility; Fertility - drug effects; Fetal Viability - drug effects; Fetuses; Germ cells; Immunoreactivity; Implantation; Leukemia; Leukemia, Promyelocytic, Acute - drug therapy; Leydig cells; Leydig Cells - drug effects; Leydig Cells - metabolism; Male; Males; Mice; Morphology; Nuclei; Oxides - administration & dosage; Oxides - toxicity; Plasma levels; post-implantation loss; Promyeloid leukemia; Rare diseases; Receptors, Androgen - metabolism; Reproduction - drug effects; Reproductive system; Seminiferous Epithelium - drug effects; Seminiferous Epithelium - metabolism; Sperm; sperm malformation; Spermatocytes; Spermatogenesis; Spermatogenesis - drug effects; Spermatozoa; Spermatozoa - drug effects; Spermatozoa - metabolism; Stem cell transplantation; Stem cells; Testes; Testis - drug effects; Testis - metabolism; Testosterone; Toxicity; Toxicity Tests, Subchronic; toxicology; Viability; Water treatment; Weight Gain - drug effects
• ISSN: 1528-7394; 1087-2620; 2381-3504
• DOI: 10.1080/15287394.2017.1376405

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 (As 2 O 3 ) 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 As 2 O 3 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, As 2 O 3 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 As 2 O 3 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 As 2 O 3 subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As 2 O 3 (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 As 2 O 3 -treated males. Data indicate that As 2 O 3 exposure altered the spermatogenic process and subsequently fetal viability.