Testicular Toxicity of Water Pipe Smoke Exposure in Mice and the Effect of Treatment with Nootkatone Thereon

Abstract

There is a worldwide increase in the popularity of water pipe (shisha) tobacco smoking including in Europe and North America. However, little is known about the effects of water pipe smoke (WPS) exposure on male reproductivity. We have recently demonstrated that WPS exposure in mice induces testicular toxicity including inflammation and oxidative stress. Nootkatone, a sesquiterpenoid found in grapefruit, has antioxidant and anti-inflammatory effects. However, the possible protective effect of nootkatone on WPS-induced testicular toxicity has not been reported before. Here, we tested the effects of treatment of mice with nootkatone on WPS-induced testicular toxicity. Mice were exposed to normal air or WPS (30 minutes/day, for 30 days). Nootkatone (90 mg/kg) was given orally to mice by gavage, 1 h before WPS or air exposure. Nootkatone treatment significantly ameliorated the WPS-induced increase in plasma levels of inhibin, uric acid, and lactate dehydrogenase activity. Nootkatone also significantly mitigated the decrease in testosterone, androgen-binding protein, and estradiol concentrations in the plasma induced by WPS. In testicular homogenates, WPS exposure caused a decrease in the total nitric oxide level and an increase in the proinflammatory cytokine interleukin-1β level and oxidative stress markers including malondialdehyde, cytochrome C, and 8-Oxo-2′-deoxyguanosine. All the latter effects were significantly alleviated by nootkatone treatment. Moreover, in testicular homogenate, nootkatone inhibited the expression of nuclear factor-kappaB induced by WPS. Likewise, histological examination of mouse testes showed that nootkatone treatment ameliorated the deterioration of spermatogenesis induced by WPS exposure. We conclude that nootkatone ameliorated the WPS-induced testicular inflammation and oxidative stress and hormonal and spermatogenesis alterations.

Nose-Only Water-Pipe Smoke Exposure in Mice Elicits Renal Histopathological Alterations, Inflammation, Oxidative Stress, DNA Damage, and Apoptosis

“…Furthermore, we found a significant increase in the concentration of cytochrome C in kidney homogenates. It has been demonstrated that exposure of mice to WPS induces oxidative stress leading to an elevation in cytochrome C release in testicular and heart tissue homogenates suggesting mitochondrial damage (Nemmar et al, 2017c;Ali et al, 2019). In addition, it has been shown that the cytokine tumor-necrosis factor α triggers cytochrome C release of from the mitochondria to the cytoplasm, which is known to attach with the adaptor apoptotic protease activator factor-I and recruit caspase-9/3 that eventually result in cellular apoptosis (Yu et al, 2014;Savitskaya and Onishchenko, 2015).…”

Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice

“…Moreover, NKT significantly reduced the activities of inflammatory enzymes such as superoxide dismutase (SOD), glutathione S-transferase (GST), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and levels of glutathione (GSH), in addition to decreasing the total antioxidant capacity (T-AOC), as well as concentrations of malondialdehyde (MDA) and nitric oxide (NO) through inhibition of the Toll-like receptor 4/NF-κB/domains-containing-protein-3-inflammasome (TLR4/NF-κB/NLRP3) pathway [23]. NTK (90 mg Kg) was also shown to reduce the anti-inflammatory effects of cigarette vapor [24], as well as inhibit lung inflammation parameters via NF-κB inhibition [19]. Nevertheless, the mechanisms underlying the effects of NTK as an anti-inflammatory compound remain to be fully characterized.…”

Kaempferol Protects Cell Damage in In Vitro Ischemia Reperfusion Model in Rat Neuronal PC12 Cells

“…After three-time washing, cells were analyzed using a flow cytometer. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) activity, glutathione (GSH) level, and glutathione disulfide (GSSG) level were determined using commercial assay kits (Biovision, USA) according to the manufacturer's protocols as previously reported [16][17][18].…”