Ginkgo biloba supplement abates lead-induced endothelial and testicular dysfunction in Wistar rats via up-regulation of Bcl-2 protein expression, pituitary-testicular hormones and down-regulation of oxido-inflammatory reactions

One of the earliest metals that humans discovered was a heavy metal called lead (Pb), which is found naturally abundant on the earth crust [1]. In antiquity, most water pipes were coated with lead including bathroom linings as well as decorative items. However, from the middle of the eighteenth century's industrial revolution, lead usage and production have greatly increased internationally causing major environmental lead leakage and build-up [1], [2]. Lead poisoning has emerged as a major global health problem since lead discovery many years ago [3], [4]. It's crucial to keep in mind that in the Model List by World Health Organization (WHO) on environmental toxicant to avoid, lead was listed [4], [5]. Additionally, lead is classified second among dangerous substances in terms of priority according to the US Agency for Toxic Substances and Disease Registry [5]. According to D’souza et al. [6], lead exposure in humans typically occurs when they consume contaminated food/drink or breathe in lead contaminated dust from the environment. Numerous studies have demonstrated that lead has detrimental effects on several organ and systems including the nervous, reproductive and cardiovascular systems [7], [8], [9].

Blood flow, tissue perfusion, blood fluidity, macromolecular permeability and some other crucial functions are all regulated by the endothelium [10], [11]. However, tissue damage, thrombosis and atherosclerosis are all symptoms of endothelial dysfunction. Long-term exposure to lead in laboratory animals results in circulatory malfunction that hastens the development of atherosclerotic disease and raises blood pressure [12], [13]. It has been shown that lead can harm the endothelium by increasing inflammation, inducing oxidative stress and most importantly, it interfere with the activity of endothelial nitric oxide synthase (eNOS), a vasoactive enzyme, which produces nitric oxide (NO), a factor that relaxes the endothelium [12]. Aside from modifications in transport and intracellular distribution of calcium, endothelial dysfunction as a result of lead exposure has also been linked to hyperactivity of vasoactive hormones such as endothelin-I [14]. There are data that suggest that NO acts as a feedback messenger to encourage hyperactivity of glutamatergic signalling, which may eventually result in excitotoxicity and peroxynitrite-induced oxidative and nitrergic damage respectively [10]. Tumor necrosis factor-alpha (TNF-α) and glutamate, which are released synergistically and co-operatively by the vascular system and encourage the development of cardiovascular diseases such as atherosclerosis, hypertension and congestive heart failure, may exacerbate endothelial dysfunction [12].

A growing body of research has connected testicular dysfunction to dysregulation of the luteinizing hormone (LH), testosterone and follicle-stimulating hormone (FSH) pathways as well as reduced tissue perfusion [15], [16]. Lead exposure causes reproductive harm to the pituitary-testicular axis which lowers sperm counts and causes hormonal abnormalities leading to infertility [17], [18], [19]. Lead exposure has also been associated with aberrant sperm shape and structure, spermatogonia, spermatocyte degeneration and necrosis because of low testosterone levels [18], [20], [21]. Lead inhibits steroidogenesis and spermatogenesis in Leydig cells by inhibiting the activity of steroidogenic enzymes [22], [23], [24]. More specifically, lead affects the synthesis and degradation of LH, FSH and testosterone [25], [26]. The negative influence of lead on the epididymis is related to change in sperm maturation via up-regulating executioner caspase-3 protein expression in testicular tissue, decreased antioxidant enzyme activity and cell membrane lipid peroxidation [19], [27]. Antioxidants have been shown to remove free radicals and minimize their negative effects as well as preventing or restricting molecular oxidation in cells and tissues caused by reactive oxygen species (ROS) [28], [29]. Antioxidant activity and free radical avoidance are crucial to prevent testicular toxicity [19], [30], [31], [32], [33]. Antioxidants and other anti-free radical drugs have been recommended for the treatment of heavy metal poisoning [29], [34], [35], [36]. To stop tissue damage brought on by free radicals, there has recently been an increase in interest in the medical use of antioxidant-rich plant products like Ginkgo biloba supplements [37], [38].

Ginkgo biloba supplement (GBS) is a famous commercial medical herb derived from the ginkgo tree's green leaves, which are one of the world's oldest surviving plant species [8]. High levels of terpene trilactones (ginkgolides A, B, C, J, M, K, L, P and Q including bilobalide) and flavonoid glycosides (myricetin, kaempferol, apigenin, quercetin, tamarixetin and isorhamnetin) may contribute to the therapeutic potential of GBS [39], [40], [41]. GBS enhances blood flow while lowering platelet activating factor according to in vivo research [40]. It guards the cell membrane against oxidative stress and the harmful effects of ischemia and reperfusion on the heart and brain [42]. GBS is frequently used in clinical practice to treat neurological and cardiovascular disorders such as Alzheimer's disease, abyrinthopathies and Parkinson disease [8], [43]. Notwithstanding, Hepatoprotective, anti-inflammatory, and antioxidant activities of GBS has also been reported [44], [45], [46], [47], [48]. In spite of these benefits, the mechanism by which GBS prevents lead-induced endothelial and testicular dysfunction is unknown. However, this present study investigated the impact of GBS on lead-induced endothelial and testicular dysfunctions.

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