Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway. Intriguingly, IDO is constitutively and highly expressed in the mammalian epididymis in contrast to most other tissues where IDO is induced by proinflammatory cytokines, such as interferons. To gain insight into the role of IDO in the physiology of the mammalian epididymis, we studied both wild type and Ido1 ؊/؊ -deficient mice. In the caput epididymis of Ido1؊/؊ animals, the lack of IDO activity was not compensated by other tryptophan-catabolizing enzymes and led to the loss of kynurenine production. The absence of IDO generated an inflammatory state in the caput epididymis as revealed by an increased accumulation of various inflammation markers. The absence of IDO also increased the tryptophan content of the caput epididymis and generated a parallel increase in caput epididymal protein content as a consequence of deficient proteasomal activity. Surprisingly, the lack of IDO expression had no noticeable impact on overall male fertility but did induce highly significant increases in both the number and the percentage of abnormal spermatozoa. These changes coincided with a significant decrease in white blood cell count in epididymal fluid compared with wild type mice. These data provide support for IDO playing a hitherto unsuspected role in sperm quality control in the epididymis involving the ubiquitination of defective spermatozoa and their subsequent removal.Indoleamine 2,3-dioxygenase (IDO) 3 (EC 1.13.11.42) is the first and rate-limiting enzyme in Trp catabolism through the kynurenine pathway (Fig. 1). IDO is a ubiquitously expressed cytoplasmic protein typically activated by interferons (IFNs) (1-5). There is ample evidence that IDO mediates potent immunosuppression in classical immune responses as well as in fetal tolerance, tumor immune resistance, and regulation of autoimmune responses (1-3, 6 -8).Thirty years ago, Yoshida et al. (9) reported that rodent epididymal protein extracts exhibited a high IDO activity. Later, Takikawa et al. (10) demonstrated that unlike the classical cytokine-mediated expression of IDO encountered in nearly all mammalian tissues, the epididymal expression of IDO was constitutive and independent of IFN-␥. More recently, we have shown that IDO is expressed in a regionalized manner by both the principal and the apical cells of the most proximal epididymal region, the caput epididymis. To gain insights into the functions of IDO and the intermediates of the kynurenine pathway in the physiology of the mammalian epididymis, we measured the expression of IDO and related enzymes as well as the abundance of kynurenines and other Trp metabolites in both wild type (WT) and Ido1 Ϫ/Ϫ male mice. These data were correlated with light and electron microscopic analyses of epididymal epithelium, sperm count, sperm morphology, and fertility.

Electronic cigarettes (e-cigarettes) are becoming the fashionable alternative to decrease tobacco smoking, although their impact on health has not been fully assessed yet. The present study was designed to compare the impact of e-cigarette refill liquid (e-liquid) without nicotine to e-liquid with nicotine on rat testis. For this purpose, e-liquid with nicotine and e-liquid without nicotine (0.5 mg/kg of body weight) were administered to adult male Wistar rats via the intraperitoneally route during four weeks. Results showed that e-liquid with or without nicotine leads to diminished sperm density and viability, such as a decrease in testicular lactate dehydrogenase activity and testosterone level. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis identified a reduction in cytochrome P450 side-chain cleavage (P450 scc) and 17 beta-hydroxysteroid dehydrogenase (17βHSD) mRNA level, two key enzymes of steroidogenesis. Following e-liquid exposure, histopathological examination showed alterations in testis tissue marked by germ cells desquamation, disorganization of the tubular contents of testis and cell deposits in seminiferous tubules. Finally, analysis of oxidative stress status pointed an outbreak of antioxidant enzyme activities such as superoxide dismutase, catalase and gluthatione-S-transferase, as well as an important increase in sulfhydril group content. Taken together, these results indicate that e-liquid per se induces toxicity in Wistar rat testis, similar to e-liquid with nicotine, by disrupting oxidative balance and steroidogenesis.

The epididymis maintains a state of immune tolerance towards spermatozoa while also protecting them and itself against infection and acute inflammation. The immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (Ido1) participates in this delicate local equilibrium. Using the mouse Ido1−/− model, we show here that the absence of IDO1 expression leads in the epididymis but not in serum to (1) an increase in the inflammatory state as evidenced by changes in the content of cytokines and chemokines, (2) the engagement of a Th1-driven inflammatory response as evidenced by changes in the Th17/Treg as well as Th1/Th2 equilibria, as well as (3) differences in the content of lipid intermediates classically involved in inflammation. Despite this more pronounced inflammatory state, Ido1−/− animals succeed in preserving the local epididymal immune situation due to the activation of compensatory mechanisms that are discussed.

This study was conducted to evaluate the effects of e-cigarette refill liquid administration alone or with nicotine on the antioxidant defense status, functional and histopathological changes in adult rat liver tissue. For this purpose, 32 rats were treated for 28 days as follows: control group was injected intra-peritoneally with physiological saline; e-cigarette 0% treated group received an intra-peritoneal injection of e-liquid without nicotine diluted in physiological saline, e-cigarette-treated group received an intra-peritoneal injection of e-liquid containing 0.5 mg of nicotine/kg of body weight/day diluted in physiological saline and nicotine-treated group received an intra-peritoneal injection of 0.5 mg of nicotine/kg of body weight/day diluted in physiological saline. In e-liquid without nicotine-exposed group, activities of the liver biomarkers aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase increase. Interestingly, oxidative stress indicators showed decreased total protein content, associated with a reduction in the antioxidant enzymes activities superoxide dismutase, catalase and glutathione-S-transferase, and an elevation in malondialdehyde content, highlighting the promotion of lipid peroxidation and oxidative stress. Histological studies identified inflammatory cells infiltration and cell death. Thus, e-liquid seems to promote oxidative tissue injuries, which in turn lead to the observed histopathological finding. In comparison, nicotine alone induced less oxidative stress and less histopathological disorders, whereas e-liquid with nicotine gave rise to more histopathological injuries. Thereby, e-liquid, per se, is able to induce hepatotoxicity and supplementation with nicotine worsens this state.

No abstract

Electronic cigarettes (e-cigarettes) are devices intended to substitute conventional cigarettes, with the aim of being less harmful. In a previous report, we showed that intraperitoneal (i.p.) injection of e-cigarette liquid (E-liquid), with or without nicotine, induced toxicity in the testes of Wistar rats by disrupting oxidative balance and steroidogenesis. In the present work, we further evaluated the impact of e-liquid with or without nicotine on the epididymis of rats using the same procedure. Results showed that e-liquid treatments led to alteration of semen parameters, with a significant drop of at least 50% in sperm vitality, a significant increase of morphologically abnormal spermatozoa and an imbalance of redox status in comparison to the control group. A significant raise of 1.4 fold, compared to the untreated rats, in myeloperoxidase (MPO) granules after both treatments was recorded, suggesting an inflammatory state. Histopathological examination confirmed a marked reduction in sperm count in the cauda epididymis. Data of this study suggest that the pro-oxidant properties of e-liquid with or without nicotine, in addition to testicular defects, could lead to an inflammatory state in the epididymis, causing alterations in the semen parameters. These data provide additional information on the impact of e-liquid on the reproductive system.