Reproductive toxic effects and possible mechanisms of zonisamide in male rats

Abstract

<jats:p> Zonisamide (ZNS) is an anticonvulsant which is used to treat the symptoms of epilepsy. Although it is frequently used during reproductive ages, studies that investigated the effects of ZNS on reproductive system are limited. Therefore, we aimed to assess the effects of ZNS on male reproductive system by oral administration to rats in 25, 50, and 100 mg/kg doses for 28 days. After the exposure period, sperm concentration, motility, morphology, and DNA damage, as biomarkers of reproductive toxic effects, were determined, and histopathological examination of testis was performed. In addition, levels of the hormones that play a role in the regulation of reproductive functions, such as follicle-stimulating hormone, luteinizing hormone (LH), and testosterone were measured and the levels of oxidative stress biomarkers that take part in the reproductive pathologies such as catalase, superoxide dismutase, glutathione, and malondialdehyde, were determined. Reproductive toxic effects related to ZNS administration were shown by the significant decrease of sperm concentration and normal sperm morphology in ZNS groups. Additionally, pathological findings were observed in the testicular tissues of ZNS-administered groups dose dependently. In addition, serum LH and testosterone levels were significantly decreased in the ZNS groups. Decreased catalase activities and increased malondialdehyde levels in ZNS groups were evaluated as oxidative stress findings in the testis tissue. It could be expressed that ZNS administration induced dose-dependent reproductive toxic effects in rats, and pathological findings associated with the reproductive system could be the result of that hormonal changes and testicular oxidative stress, which in turn might be considered as possible mechanisms of male reproductive toxicity. </jats:p>

Endocrine disruption: Reproductive toxicity of glyceryl trinitrate and isosorbide mononitrate in male Wistar rats

“…A number of previous studies reported that antioxidants were the cellular defence mechanisms against oxidative stress and any decline in their function elevated the level of oxidative stress that led to reproduction failure (Barati et al, 2020; Martin‐Hidalgo et al, 2019). Oxidative status is reflected by the measurement of the amount of antioxidants from the sample of testes along with the MDA levels (the end‐product of lipid peroxidation) (Karaduman et al, 2019) In the current study, we found a decline of CAT activity and increase of MDA level in GTN and IM treated group of rats at all dose levels in comparison to control group that was evident of the oxidative stress in testes caused by sub‐chronic exposure of these drugs. The elevated level of the oxidative stress is testes is known to inhibit sperm production thereby causing sperm function decline.…”

Long‐term stiripentol administration, an anticonvulsant drug, does not impair sperm parameters in rats

“…Anti‐epileptic drugs may affect the reproductive system via many different mechanisms (Herzog, 2008; Svalheim et al., 2015). Acting in the central nervous system, AEDs may alter the concentration of neurotransmitters and thus impair secretion of hormones by the hypothalamus and pituitary gland (Baysal et al., 2017; Karaduman et al., 2019). AEDs metabolised in the liver may increase catabolism of sex hormones and/or alter the level of the sex hormone‐binding globulin (SHBG), and thus affect the level of biologically active testosterone and oestradiol (Herzog, 2008; Svalheim et al., 2015).…”

“…AEDs metabolised in the liver may increase catabolism of sex hormones and/or alter the level of the sex hormone‐binding globulin (SHBG), and thus affect the level of biologically active testosterone and oestradiol (Herzog, 2008; Svalheim et al., 2015). Also, a direct toxic effect of AEDs on gonads is possible, as well as a direct influence on semen quality (Asadi‐Pooya et al., 2015; Baysal et al., 2017; Hamed et al., 2015; Karaduman et al., 2019; Ocek et al., 2018). It has been reported that carbamazepine, valproate and phenytoin impair the function of sperm membrane and reduce sperm motility (Semet et al., 2017).…”

“…It cannot be excluded that stiripentol may stimulate antiapoptotic activity. It has been reported that oxcarbazepine can also exert beneficial influence on the sperm parameters (Wu et al., 2018), whereas many other AEDs seem to be spermatotoxic (Asadi‐Pooya et al., 2015; Baysal et al., 2017; Hamed et al., 2015; Karaduman et al., 2019). It is well known that mitochondrial dysfunction leads to many changes within mitochondria and within mitochondrial membrane resulting first in so‐called mitoptosis and later to apoptosis (Mokrousov et al., 2019).…”

Carbamazepine adversely altered the pituitary–testicular axis with resultant reproductive dysfunctions than levetiracetam or carbamazepine–levetiracetam adjuvant treatment in male Wistar rat

“…However, prolonged AED administration is reportedly associated with a diverse adverse effect such as behavioural/psychiatric disorders (Lee, 2019), metabolic disruption (St Louis, 2009), hepatotoxicity (Ayalew & Muche, 2018), and alterations in bone turnover markers (Arora et al., 2016) to mention but a few. Moreover, sexual dysfunction and reproductive disorders are more common among patients with epilepsy than any typical population (Atif et al., 2016; Isojärvi, 2008; Luef, 2010; Wu et al., 2018), while there are consistent pieces of evidence on the adverse effect of some AEDs particularly on the testicular dysfunction (Akinsomisoye et al., 2017; Osuntokun et al., 2017), deregulation of sex hormones (Herzog et al., 2017), reproductive toxicity (Bairy et al., 2010; Karaduman et al., 2019), and reduction of seminal quality (Falokun et al., 2010).…”