Vitamin B12 Prevents Cimetidine-Induced Androgenic Failure and Damage to Sperm Quality in Rats

Abstract

Cimetidine, used as an anti-ulcer and adjuvant treatment in cancer therapy, causes disorders in the male reproductive tract, including steroidogenesis. However, its effect on sperm quality and male fertility has been poorly addressed. Since vitamin B 12 has demonstrated to recover spermatogonia number and sperm concentration in cimetidine-treated rats, we evaluated the impact of cimetidine on sperm quality and fertility potential and whether vitamin B 12 is able to prevent the harmful effect of this drug on steroidogenesis and sperm parameters. Adult male rats were treated for 52 consecutive days as follows: cimetidine group (100 mg/kg of cimetidine), cimetidine/vitamin B 12 group (100 mg/kg of cimetidine + 3 μg vitamin B 12 ), vitamin B 12 group (3 μg vitamin B 12 ) and control group (saline). Serum testosterone levels and immunofluorescence associated to western blot for detection of 17β-HSD6 were performed. Sperm morphology and motility, mitochondrial activity, acrosome integrity, DNA integrity by Comet assay, lipid peroxidation as well as fertility potential were analyzed in all groups. Apoptotic spermatids were also evaluated by caspase-3 immunohistochemistry. In the cimetidine-treated animals, reduced serum testosterone levels, weak 17β-HSD6 levels and impaired spermiogenesis were observed. Low sperm motility and mitochondrial activity were associated with high percentage of sperm tail abnormalities, and the percentage of spermatozoa with damaged acrosome and DNA fragmentation increased. MDA levels were normal in all groups, indicating that the cimetidine-induced changes are associated to androgenic failure. In conclusion, despite the fertility potential of rats was unaffected by the treatment, the sperm quality was significantly impaired. Therefore, considering a possible sperm-mediated transgenerational inheritance, the long term offspring health needs to be investigated. The administration of vitamin B 12 to male rats prevents the androgenic failure and counteracts the damage inflicted by cimetidine upon sperm quality, indicating that this vitamin may be used as a therapeutic agent to maintain the androgenic status and the sperm quality in patients exposed to androgen disrupters.

The effect of vitamin B12 supplement on post‐thaw motility, viability and DNA damage of human sperm

“…Vitamin B12 increases the antioxidant capacity, and it provides the protection against the lipid peroxidation through the increase in glutathione peroxidase activity (Alzoubi et al., 2014; Lagemaat et al., 2019). Vitamin B12 is able to recover the seminiferous epithelium of animals treated with cimetidine, increasing the number of spermatogonia and spermatocytes (Beltrame et al., 2019; Beltrame & Sasso‐Cerri, 2017). Hu et al found out adding vitamin B12 (2.5 mg/ml) to extender in bull and can increase motility and viability of spermatozoa (Hu et al., 2009).…”

“…Also, it is determined that vitamin B12 can protect DNA against paclitaxel‐induced genotoxicity and oxidative damage (Alzoubi et al., 2014). In 2019 demonstrated the administration of vitamin B12 to male rats prevents the androgenic failure and counteracts the damage inflicted by cimetidine (including DNA fragmentation) upon sperm quality (Beltrame et al., 2019). Recent studies have shown that vitamin B12 modulated oxidative stress responses through the increasing methionine synthase activity related to glutathione synthesis (Karamshetty et al., 2016; Manzanares & Hardy, 2010).…”

“…Thus, this vitamin can protect DNA against free radicals (Alzoubi et al., 2014; Banihani, 2017; Richard et al., 2009; Lagemaat et al., 2019). Some studies showed that using diet vitamin B12 improves sperm quality (particularly sperm count) (Beltrame et al., 2019; Beltrame & Sasso‐Cerri, 2017; Gual‐Frau et al., 2015). Also articles showed the protective effect of vitamin B12 supplementation during sperm freezing in animal model (Asadpour et al., 2012; Hamedani et al., 2013; Hu et al., 2009).…”

“…In 2019, Beltrame et al showed that vitamin B12 may be a potential therapeutic agent for the maintenance of sperm quality and the androgenic status of patients exposed to androgen disrupters (Beltrame et al., 2019). In 2013, an oral antioxidant treatment including vitamin B12 caused to increase sperm quality (Abad et al., 2013).…”

Cisplatin induced testicular damage through mitochondria mediated apoptosis, inflammation and oxidative stress in rats: impact of resveratrol

“…Sperm viability was specified using eosin/nigrosine stain as previously mentioned [29] and the percentage viability was calculated [30]. The total abnormality of sperm head and tail was expressed as percentage [31].…”