Mechanistic insight into the protective effects of fisetin against arsenic-induced reproductive toxicity in male rats

Abstract

Arsenic is one of the most hazardous environmental contaminants, which adversely affects the dynamics of male reproductive system. Fisetin (FIS) is a bioactive flavonoid, which is known to exert strong antioxidative effects. Therefore, the current research was planned to evaluate the alleviative efficacy of FIS against arsenic-induced reproductive damages. Forty-eight male albino rats were divided into 4 groups (n = 12), which were treated as follows: (1) Control, (2) Arsenic-intoxicated group (8 mg kg−1), (3) Arsenic + FIS-treated group (8 mg kg−1 + 10 mg kg−1), and (4) FIS-treated group (10 mgkg−1). After 56 days of treatment, the biochemical, lipidemic, steroidogenic, hormonal, spermatological, apoptotic and histoarchitectural profiles of rats were analyzed. Arsenic intoxication reduced the enzymatic activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GSR), in addition to glutathione (GSH) level. Conversely, the levels of thiobarbituric acid reactive substance (TBARS) and reactive oxygen species (ROS) were increased. Moreover, it escalated the level of low-density lipoprotein (LDL), triglycerides and total cholesterol, while declining the level of high-density lipoprotein (HDL). Furthermore, steroidogenic enzymes expressions, 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD, steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (CYP11A1) and 17α-hydroxylase/17, 20-lyase (CYP17A1), were found to be reduced, which brought down the level of testosterone. Besides, the levels of gonadotropins (LH and FSH) were decreased. Additionally, a decline in sperm mitochondrial membrane potential (MMP), motility, epididymal sperm count and hypo-osmotic swelling (HOS) coil-tailed sperms was observed, whereas the dead sperms and structural damages (head, midpiece and tail) of sperms were escalated. Moreover, arsenic exposure up-regulated the mRNA expressions of apoptotic markers, namely Bax and caspase-3, whereas lowered the expression of anti-apoptotic marker, Bcl-2. In addition, it induced histoarchitectural changes in testes of rats. However, FIS treatment resulted in remarkable improvements in testicular and sperm parameters. Therefore, it was inferred that FIS could serve as a therapeutic candidate against arsenic-generated male reproductive toxicity attributing to its anti-oxidant, anti-lipoperoxidative, anti-apoptotic, and androgenic efficacy.

Reproductive and Developmental Effects of Sex-Specific Chronic Exposure to Dietary Arsenic in Zebrafish (Danio rerio)

“…Consistent with our observations, arsenic has been found to downregulate the mRNA expression of sf-1 and the steroidogenic enzymes in the testicular Leydig cells of mice [ 61 , 62 ]. Previous rodent studies also reported reduced expression of the gonadal 17β-hsd gene and a decrease in the plasma sex steroid levels following chronic treatment with arsenic [ 26 , 63 , 64 ]. Additionally, we also recorded a decreased expression of gonadotropin receptor genes ( Fshr and Lhr ) in the gonads of male and female zebrafish following chronic exposure to arsenic, which might be a consequence of the downregulation of the Fshβ and Lhβ genes in the brain, as suggested in mammalian studies [ 65 ].…”

“…A few previous studies conducted in fish also indicated the endocrine-disrupting effects of arsenic. For example, an in vitro study using a fish testicular culture system suggested that arsenic inhibits the synthesis of the androgenic sex hormone (11-ketotesterone), leading to decreased spermatogenesis in males [ 26 ]. In female oviparous vertebrates like fish, reproduction is regulated by the HPG-L (hypothalamus–pituitary–gonad–liver) axis, as the liver plays a primary reproductive function by synthesizing and secreting vitellogenin under estrogen stimulation [ 27 ].…”

Fisetin Treats Kidney Oxidative Stress, Inflammation, and Apoptosis in Rat Diarrhea

“…Additionally, according to a number of previous studies, including Ren et al [32], the antioxidant activity of fisetin was thought to be responsible for these protective effects. Fur-thermore, fisetin was observed by Ijaz et al [67] to enhance the enzymatic activity of reactive oxygen species, thiobarbituric acid reactive substance, glutathione, glutathione reductase, superoxide dismutase, and catalase. Moreover, Wang et al [68] reported that fisetin had anti-inflammatory and anti-fibrotic properties, hence, fisetin can protect the kidneys from developing fibrotic disorders.…”