ABSTRACT
The pathophysiology of hypertension is complex and multifactorial, and includes exposure to various chemical substances. Several recent studies have documented the reproductive and neurological toxicities of 1-bromopropane (1-BP). Given that 1-BP increased reactive oxygen species in the brain of rats, we hypothesized that 1-BP also has cardiovascular toxicity through increased oxidative stress. To test this hypothesis, male F344 and Wistar Nagoya rats (n = 7-8 per group per test) were exposed to 0 or 1000 ppm of 1-BP via inhalation for 4 weeks (8 h per day, 7 days per week). The exposure to 1-BP increased systolic blood pressure. This effect was associated with a significant decrease in the reduced/oxidized glutathione ratio. A significant increase in nitrotyrosine levels, activation of the NADPH oxidase pathway, which was evidenced by upregulation of gp91phox, a NADPH oxidase subunit, and significant decreases in the expressions of antioxidant molecules such as Cu/Zn- and Mn-superoxide dismutase catalase, and nuclear factor erythroid 2-related factor 2, were observed in the aortas of Wistar Nagoya rats exposed to 1-BP. Our results indicate that subacute (4-week) inhalation exposure to 1-BP increases blood pressure and suggest that this cardiovascular toxic effect is due, at least in part, to increased oxidative stress mediated through activation of the NADPH oxidase pathway. Further study is needed to assess whether NADPH oxidase activation causes the increase in blood pressure in the rats exposed to 1-BP. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Air Pollutants/toxicity , Blood Pressure/drug effects , Inhalation Exposure/adverse effects , Oxidative Stress/drug effects , Animals , Antioxidants/metabolism , Endothelium, Vascular/drug effects , Gene Expression/drug effects , Hydrocarbons, Brominated/toxicity , Inhalation Exposure/analysis , Male , NADPH Oxidases/genetics , Rats, Inbred F344 , Rats, WistarABSTRACT
1-Bromopropane (1-BP), an alternative to ozone-depleting solvents, exhibits neurotoxicity and reproductive toxicity in animals and humans. The present study investigated the effects of exposure to 1-BP on expression of neurotransmitter receptor genes in the rat brain to explore possible biomarkers for central neurotoxicity and find brain regions sensitive for microarray analysis. Thirty-six F344 rats were divided at random into four equal groups of nine and exposed to 1-BP at 0, 400, 800 and 1000 ppm for 8 h/day; 7 days/week for 4 weeks. Total RNA from different brain regions was extracted and real-time PCR was conducted to quantify the mRNA levels of serotonin, dopamine and GABA receptors. Western blot analysis for specific regions of interest was also carried out to determine the protein levels. The mRNAs of 5HTr2a, D2R and GABAa1 were down regulated in a 1-BP dose-dependent manner in the hippocampus. The mRNA levels of 5HTr1a, 5HTr2a, D1R and GABAa1 were significantly decreased in the cortex of rats exposed to 800 ppm, but not to 1000 ppm. The mRNAs of 5HTr1a and 5HTr3a in the pons-medulla were decreased in rats exposed to 400 ppm or higher concentrations. The mRNA expression of D2R in the hippocampus and 5HTr1a and 5HTr3a in the pons-medulla oblongata were the most sensitive indicators of 1-BP neurotoxicity. The results suggest that mRNA expression analysis is useful in identifying brain regions susceptible to 1-BP, as well as providing potential biomarkers for central nervous system toxicity.
Subject(s)
Brain/drug effects , Gene Expression Regulation/drug effects , Receptors, Neurotransmitter/metabolism , Administration, Inhalation , Analysis of Variance , Animals , Brain/anatomy & histology , Dose-Response Relationship, Drug , Hydrocarbons, Brominated/toxicity , Male , RNA, Messenger/metabolism , Rats , Rats, Inbred F344 , Receptors, Neurotransmitter/geneticsABSTRACT
Previous experiments indicated that 1-bromopropane (1-BP), an alternative to chloroflurocarbons, is neurotoxic and inhibits spermiation in the testis. Here we investigated the reversibility of the toxic effects of 1-BP in rats. Male Wistar rats were divided into three equal groups of 24 each and exposed by inhalation to 0, 400 or 1000 ppm of 1-BP for 6 weeks (8 hrs/day, 7 days/week). Eight rats from each group were sacrificed at the end of 6 weeks exposure, and at 4 and 14 weeks after the end of exposure, to assess the recovery processes. We studied sperm count, motility, morphology and testicular histopathology, as well as blood pressure, skin temperature and hindlimb muscle strength. At the end of 6 weeks of exposure to 1000 ppm (0 week recovery), testicular weight, epididymal weight, sperm count and motility were low, morphologically abnormal sperm were increased and spermatogenic cells showed diffuse degeneration. These changes did not show full recovery at 14 weeks recovery, with the exception of the prostate and seminal vesicular weights, which recovered back to control values. At 400 ppm, increased retained spermatids at 0 week recovery returned to normal at 4 weeks recovery. Exposure to 1000 ppm produced sustained reduction of hindlimb muscle strength at 14 weeks recovery, whereas normalization of the skin temperature and blood pressure was noted after transient changes. Our study showed that the effect of 1-BP on spermatogenesis is dose-dependent; low exposure inhibited spermiation and hormone-dependent organ weight reduction and these changes were transient, while a higher dose of 1000 ppm 1-BP caused persistent depletion of spermatogenic cells.