Aroclor 1254 impairs spermatogenesis and induces oxidative stress in rat testicular mitochondria.
ABSTRACT Aroclor 1254 (A1254) has been shown to have potential testicular toxicity. The mechanism of action of A1254 on male reproduction is not clear. The present study was designed to investigate the potential toxicity of A1254 on rat spermatogenesis. Oxidative stress was also assessed in testicular mitochondria as an underlying mechanism. Adult male Wistar rats were injected with A1254 (0, 0.75, 1.5 or 3mg/kg/day i.p.) or with vehicle (corn oil) for 20 consecutive days. A1254 at doses of 1.5 and 3mg/kg/day resulted in a significant decrease in body weight, testes weight, epididymal and relative epididymal weight. Similarly, the relative testis weight was significantly decreased at 3mg/kg/day. Sperm count, motility and daily sperm production were significantly decreased at 1.5 and 3mg/kg/day. The same two doses significantly inhibited the activities of testicular mitochondrial CAT, GPx and GR while the activity of SOD was significantly decreased by 0.75, 1.5 and 3mg/kg/day. The levels of H(2)O(2) generation and LPO were significantly increased in mitochondria in a dose-related pattern. GSH and Vit C were significantly decreased at 0.75, 1.5 and 3mg/kg/day. In conclusion, A1254 impairs spermatogenesis as evidenced, at least partly, by induction of oxidative stress in testicular mitochondria.
Article: De-Risking of Stilbazulenyl Nitrone (STAZN), a Lipophilic Nitrone to Treat Stroke Using a Unique Panel of In Vitro Assays.[show abstract] [hide abstract]
ABSTRACT: In the present study, we used a comprehensive panel of in vitro assays to evaluate the efficacy and safety of stilbazulenyl nitrone (STAZN) as a lead compound to treat acute ischemic stroke. First, we measured neuroprotection in vitro using two different HT22 hippocampal nerve cell assays. Secondly, to de-risk drug development, we used CeeTox analysis with the H4IIE rat hepatoma cell line to determine the acute toxicity profile of STAZN. Third, STAZN was tested in microsomes from four species for measures of metabolic stability. Last, we determined the Ames test genotoxicity profile of STAZN using Salmonella typhimurium TA989 and TA100. In vitro, STAZN was neuroprotective against toxicity induced by iodoacetic acid, and oxytosis-induced glutathione depletion was initiated by glutamate, with an EC(50) value of 1-5 μM. Secondly, using CeeTox analysis, the estimated C(Tox) value (i.e., sustained concentration expected to produce toxicity in a rat 14-day repeat dose study) for STAZN was calculated to be 260 μM. Third, the half-life of STAZN in humans, dogs, and rats was 60-78 min. Last, the genotoxicity profile showed that STAZN did not induce bacterial colony growth under any conditions tested, indicating the lack of mutagenicity with this compound. STAZN appears to be a multi-target neuroprotective compound that has an excellent safety profile in both the CeeTox and Ames mutagenicity assays. STAZN may have significant potential as a novel neuroprotective agent to treat stroke and should be pursued in clinically relevant embolic stroke models.Translational Stroke Research 06/2011; 2(2):209-217.
Article: Bisphenol A Alters n-6 Fatty Acid Composition and Decreases Antioxidant Enzyme Levels in Rat Testes: A LC-QTOF-Based Metabolomics Study.[show abstract] [hide abstract]
ABSTRACT: Male reproductive toxicity induced by exposure to bisphenol A (BPA) has been widely reported. The testes have proven to be a major target organ of BPA toxicity, so studying testicular metabolite variation holds promise for the discovery of mechanisms linked to the toxic effects of BPA on reproduction. Male Sprague-Dawley rats were orally administered doses of BPA at the levels of 0, 50 mg/kg/d for 8 weeks. We used an unbiased liquid chromatography-quadrupole time-of-flight (LC-QTOF)-based metabolomics approach to discover, identify, and analyze the variation of testicular metabolites. Two n-6 fatty acids, linoleic acid (LA) and arachidonic acid (AA) were identified as potential testicular biomarkers. Decreased levels of LA and increased levels of AA as well as AA/LA ratio were observed in the testes of the exposed group. According to these suggestions, testicular antioxidant enzyme levels were detected. Testicular superoxide dismutase (SOD) declined significantly in the exposed group compared with that in the non-exposed group, and the glutathione peroxidase (GSH-Px) as well as catalase (CAT) also showed a decreasing trend in BPA treated group. BPA caused testicular n-6 fatty acid composition variation and decreased antioxidant enzyme levels. This study emphasizes that metabolomics brings the promise of biomarkers identification for the discovery of mechanisms underlying reproductive toxicity.PLoS ONE 01/2012; 7(9):e44754. · 4.09 Impact Factor