Cisplatin-induced azoospermia and testicular damage ameliorated by adipose-derived mesenchymal stem cells

BACKGROUND: The testes are highly susceptible to the adverse effects of chemotherapy and radiation at all stages of life. Exposure to these threats mainly occurs during cancer treatment and as an occupational hazard in radiation centers. The present study investigated the regenerative ability of adipose-derived mesenchymal stem cells (ADMSCs) against the adverse effects of cisplatin on the structure and function of the testes. METHODS: New Zealand white rabbits (N = 15) were divided into three groups of five: a negative control group (no treatment), a cisplatin group (single dose of cisplatin into each testis followed three days later by a PBS injection), and a cisplatin + ADMSCs group (cisplatin injection followed three days later by an ADMSC injection). On day 45 post-treatment, serum testosterone levels were evaluated, and the testes and epididymis were collected for histology, oxidative stress examination, and epididymal sperm analysis. RESULTS: Cisplatin caused damage to the testicular tissue and decreased serum testosterone levels, epididymal sperm counts, and oxidants. An antioxidant imbalance was detected due to increasing malondialdehyde (MDA) and reduced glutathione (GSH) levels in testicular tissue. The ADMSC-treated group displayed a moderate epididymal sperm count, adequate antioxidant protection, suitable hormone levels, and enhanced testicular tissue morphology. CONCLUSIONS: ADMSCs treatment repaired damaged testicular tissue, enhanced biochemical parameters, and modified pathological changes caused by cisplatin.

Establishing a nonlethal and efficient mouse model of male gonadotoxicity by intraperitoneal busulfan injection / 亚洲男科学杂志(英文版)

An ideal animal model of azoospermia would be a powerful tool for the evaluation of spermatogonial stem cell (SSC) transplantation. Busulfan has been commonly used to develop such a model, but 30%-87% of mice die when administered an intraperitoneal injection of 40 mg kg-1. In the present study, hematoxylin and eosin staining, Western blot, immunofluorescence, and quantitative real-time polymerase chain reaction were used to test the effects of busulfan exposure in a mouse model that received two intraperitoneal injections of busulfan at a 3-h interval at different doses (20, 30, and 40 mg kg-1) on day 36 or a dose of 40 mg kg-1 at different time points (0, 9, 18, 27, 36, and 63 days). The survival rate of the mice was 100%. When the mice were treated with 40 mg kg-1 busulfan, dramatic SSC depletion occurred 18 days later and all of the germ cells were cleared by day 36. In addition, the gene expressions of glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2), chemokine (C-X-C Motif) ligand 12 (CXCL12), and colony-stimulating factor 1 (CSF1) were moderately increased by day 36. A 63-day, long-term observation showed the rare restoration of endogenous germ cells in the testes, suggesting that the potential period for SSC transplantation was between day 36 and day 63. Our results demonstrate that the administration of two intraperitoneal injections of busulfan (40 mg kg-1 in total) at a 3-h interval to mice provided a nonlethal and efficient method for recipient preparation in SSC transplantation and could improve treatments for infertility and the understanding of chemotherapy-induced gonadotoxicity.

Occupational Reproductive Function Abnormalities and Bladder Cancer in Korea

The purpose of this study was to review occupational reproductive abnormalities and occupational bladder cancer in Korea and to discuss their toxicological implications. Reproductive dysfunction as a result of 2-bromopropane poisoning was first reported in Korean workers. In 1995, 23 of the 33 workers (25 female and 8 male workers) who were exposed to 2-bromopropane during the assembly of tactile switch parts developed reproductive and/or hematopoietic disorders. A total of 17 (68%) workers were diagnosed with ovarian failure. Two of the eight male workers experienced azoospermia and four workers experienced some degree of oligospermia or reduced sperm motility. In summary, 2-bromopropane poisoning caused severe reproductive effects in Korean workers. The prognosis was poor for reproductive dysfunction. A few cases of occupational bladder cancer have been reported in Korea, whereas other cancers of the urinary tract have not been reported after occupational exposure. A few cases of benzidine-induced cancer have been reported in Korea and 592 workers in Japan have received compensation for benzidine and beta-naphthylamine-induced cancer. In conclusion, a few cases of benzidine-induced occupational bladder cancer have been reported in Korea. However, benzidine-induced bladder cancer will likely be an important occupational health issue in Korea in the coming years.

Current regimen of pulse therapy for pemphigus: minor modifications, improved results.

BACKGROUND: If administered properly, dexamethasone cyclophosphamide pulse (DCP) therapy has the potential to effect lifelong recovery from pemphigus. AIMS: The objective of this paper is to highlight various parameters of DCP therapy and also, to report the effects of a few modifications in the regimen. METHODS: An analysis of 123 patients treated with the DCP/DP regimen over a period of five years (1998 to 2002) is presented here. Seventeen patients who did not start/continue the treatment and three patients who died during the treatment have been excluded from the analysis. Twenty patients who had not yet started families were given only dexamethasone pulses (DPs) while 103 patients received DCPs. Low dose (50 mg/day) cyclophosphamide was used as in the standard regimen. The three modifications introduced into the regimen were: (1) an additional daily dose of oral betamethasone sufficient to control the disease activity during phase I, which was progressively tapered off completely as the patient recovered, (2) use of systemic antibiotics if the patient had skin lesions, and oral anti-candida drugs if the patient had oral ulcers until complete healing, and (3) insistence on thorough cleaning of the skin and scalp with a normal soap and shampoo, and proper maintenance of oral hygiene in spite of skin/mucosal lesions. The regimen consisted of DCP/DP repeated in exactly 28-day cycles, along with 50 mg cyclophosphamide per day, insistence on completing the treatment and avoiding irregular pulses in all patients. The number of DCPs/DPs during phase I varied in different patients depending upon the dose of betamethasone used and the rate of recovery, but phase II (nine DCPs/DPs in exactly 28-day cycles along with 50 mg cyclophosphamide per day) and phase III (only 50 mg cyclophosphamide per day) was fixed at nine months each. This was followed by posttreatment follow-up (phase IV). RESULTS: At present, all the patients are in complete remission. The confirmed period of posttreatment, disease-free follow-up period has already been more than five years in 62 patients, 3-5 years in 41 patients, 2-3 years in three patients and less than two years in six patients. Eight DCP patients and three DP patients developed a relapse (the relapse rates thus being 7.7 and 15% respectively) and received a second course of pulse therapy. They are also in remission at present. The duration of phase I was three months in 62 patients, 4-5 months in 28 patients, 6-9 months in 13, 10-12 months in nine patients and more than 12 months in 11 patients. The maximum daily dose of betamethasone used in these patients was nil in 17 patients, 1-2 mg in 85, 3-4 mg in 16, and> 4 mg in five patients. CONCLUSIONS: The modifications employed in this study could ensure the cure of all pemphigus patients by using DCP therapy administered at a private clinic.