MJ is the most commonly used recreational drug worldwide [13-15]. It is one of the most commonly abused substances in the USA, where 3.3% of young adults 19-28 years of age use MJ on a daily basis and 54% of people between 26 and 34 have used MJ at least once [16]. Medicinal uses of cannabis date back thousands of years, and both crude smoke and the psychoactive component, delta-9-tetrahydocannabinol (D9-THC), have been used for treating migraine headache, glaucoma, nausea, and anorexia [17]. MJ contains at least 20 active cannabinoids [18], the primary psychoactive cannabinoid being D9-THC [13, 14, 18]. Some reports suggest that, over the past 10-20 years, the cannabinoid content in MJ cigarettes may have increased severalfold [19, 20].

Despite widespread use, little information is available regarding toxic effects of MJ smoke. Persistent efforts to legalize MJ and political movements advocating medicinal uses tend to promote the notion that little or no hazardous risk is associated with MJ smoking. In vitro and whole-animal studies suggest that D9-THC has a direct immunosuppressive effect on a variety of immune cells, including macrophages, natural killer cells, and T lymphocytes [21]. Habitual MJ smoking has also been shown to alter alveolar macrophage morphology, phagocytic function, fungi-cidal and bactericidal activity, and oxidative burst superoxide production [22-24],

The expression/activity of cannabinoid receptor 1 controls the physiological alterations of DNA packaging during spermiogenesis and epididymal transit [13-15, 22-24]. Therefore, given the deleterious effects of sperm DNA damage on male fertility, the reproductive function of MJ users may also be impaired by deregulation of the endogenous endocannabinoid system [22-24] .

The endocannabinoid system regulates many functions in the human body, including reproduction. Two cannabinoid receptors have thus so far been identified—CB1 and CB2—as well as a family of lipid signaling ligands, of which anandamide, or arachidonyl ethanoamide (AEA), is the most abundant in reproductive fluids [24], The active psychotrophic ingredient of MJ, THC, acting as an antagonist and binding to these cannabinoid receptors, may upset the endogenous cannabinoid signaling pathways and thus disrupt the normal functions of reproduction [23]. CB1 receptors have been found in rat testes and mouse vas deferens [23, 24]. Therefore, they may play a possible role in the control of spermatogenesis and male fertility [25-27],

Exposure to MJ smoke causes a dramatic increase in ROS over control levels, an increase that was as much as threefold higher than the increment resulting from exposure to a similar amount of tobacco smoke [28] . Oxidizing agents prooxidants such as H2O2 are responsible for some of the MJ-induced effects. The MJ-induced ROS appeared to be cannabinoid-dependent because smoke from cigarettes lacking D9-THC produces no increase in ROS compared with control [28].

Impaired sperm motility may be due to deficient oxidative phosphorylation as a result of damaged or absent proteins in the electron transport chain subunits caused by mitochondrial deletions or base substitutions [29]. Also of note, the levels of mtDNA damage in sperm are much higher than those observed in somatic cells [30-32], suggesting that sperm may be more vulnerable to damage. Owing to the lack of histone proteins to protect the DNA against attack by ROS, mitochondria have little protection against oxidative assault, so their DNA accumulates large numbers of mutations [33]. The most immediate effect of ROS damage is in the mtDNA, as it is continually exposed to a high steady-state level of ROS and free radicals within the mitochondrial matrix [34] . It is also vulnerable because of the mitochondria's lack of repair mechanisms.

Sarafian et al. [35] reported that MJ smoke containing THC is a potent source of cellular oxidative stress that could contribute to cellular damage. Because the respiratory chain has the capacity for ROS production, an upregulation by THC may cause significant oxidative damage to mtDNA [35] .

THC alters another essential sperm function, that of the acrosome reaction, at higher recreational concentrations in the 90% fraction [33] . The inhibition of the acrosome reaction was greater in the 45% fraction at both recreational and therapeutic concentrations, suggesting again that THC has more pronounced effects on sperm that are of poorer quality [33]. THC may impair fertilization by modulating acrosome reactions at recreational concentrations.

At low doses of MJ, there is a significant increase in lipid peroxidation and decrease in testicular lipid content, but the effects are significantly less at higher doses and at the withdrawal of cannabis treatment (recovery dose) [33]. There is a marked decrease in antioxidant enzyme profiles (superoxide dismutase, catalase, and glutathione peroxidase) and glutathione (GSH) content at low doses, but these effects are higher at higher dose and at withdrawal of the treatment (recovery effect) [33, 35]. Testicular histology reveals significant shrinkage of tubular diameter and detrimental changes in seminiferous epithelium of testis with resulting lowered serum testosterone and pituitary gonadotropins (follicular stimulating [FSH] and luteinizing hormones [LH]) levels at low doses [33, 35]. But at higher doses and particularly after withdrawing the treatment, the regression of various germ cell layers of testes through may be observed, indicating that recovery effects on testes may due through the endogenous testicular antioxidant enzymes profiles and pituitary gonadotropins hormones feedback mechanisms [33] .

The generation of ROS has several undesirable consequences, including the impairment of cellular energetic and defense systems and the promotion of malignant transformation [36-38] . Cell death induced by MJ smoke is largely necrotic. These deleterious effects of MJ smoke could have serious implications for tissues in direct contact with cannabinoid-containing smoke, including lung macrophages and surface epithelial cells in the upper aerodigestive tract and the tracheobronchial mucosa. Such effects need to be taken into consideration when evaluating risk-benefit factors associated with MJ consumption.

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