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

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 (9 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-1 beta 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.