Assessment of the acute acrylonitrile-induced neurotoxicity in rats

doi:10.1016/0892-0362(91)90056-3

Neurotoxicology and Teratology

Volume 13, Issue 5, September–October 1991, Pages 499-502

https://doi.org/10.1016/0892-0362(91)90056-3 Get rights and content

Abstract

Acrylonitrile (VCN) is an aliphatic nitrile which is used extensively in manufacturing of synthetic fibers, plastics, and rubber. Although the neurotoxicity of VCN is recognized, no thorough characterization of this effect has been reported. Current studies were designed to quantiatively characterize the acute phase of VCN-induced cholinomimetic neurotoxicity, and to determine the effects of dose, route of administration, and atropine on such toxicity. Administration of a single gavage or subcutaneous doses of 20, 40, or 80 mg VCN/kg to male Sprague-Dawley rats causes two distinctive phases of acute neurotoxic effects. Signs observed in the early phase had a rapid onset, and were cholinomimetic in nature. They included salivation, lacrimation, chromodacryorrhea, polyuria, miosis, vasodilatation in face, ears and extremities, increased gastric secretion, and diarrhea. A late phase developed hours after VCN dosing, and the toxic signs included depression, convulsions, and respiratory failure followed by death at high doses. These results revealed that the cholinomimetic toxicity induced by VCN was dose related regardless of the route of administration. In another study, rats were pretreated with atropine (1 mg/kg, IP) prior to VCN (40 mg/kg) in order to investigate the role of the cholinergic system. Atropine protected rats against VCN-induced cholinomimetic neurotoxicity, suggesting possible involvement of the cholinergic system. Finally, this work provides essential basic information for studying the biochemical, pharmacological, and neurological basis of VCN-induced neurotoxicity in the rat.

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Two antagonistic sets of motoneurons innervate, in fact, the scaphognathite depressor and levator muscles controlling the ventilatory appendages (Simmers and Bush, 1983). ACN is a known Central Nervous System (CNS) depressant (Rocha et al., 2016), which in mammals can cause cholinergic toxicity through acetylcholine (ACh) mimetics and AChE inhibition (Ghanayem et al., 1991). Furthermore, in mice, ACN may compromise cell's capacity to deal with the stress, leading to a decrease in AChE activity (Yuanqing et al., 2013).
Integrated compensatory responses of physiological systems towards homeostasis are generally overlooked when it comes to analysing alterations in biochemical parameters indicative of such processes. Here an hypothesis-driven multivariate analysis accounting for interactive multibiomarker responses was used to investigate effects of long-term exposure of Carcinus maenas to Hazardous and Noxious Substances (HNS). Adult male crabs were exposed to low and high post-spill levels of acrylonitrile (ACN) or aniline (ANL) for 21d. Bioaccumulation, feeding behaviour, and biomarkers related to mode-of-action (MoA) (detoxification, neurotransmission and energy production) were evaluated over time. Distinct temporal patterns of response to low and high exposure concentrations were depicted, with a main set of interactive multibiomarker predictors identified for each HNS (five for ACN and three for ANL), useful to follow coupled evolvement of biomarker responses. ACN caused peripheral neurotoxic effects coupled with enhanced biotransformation and significant oxidative damage particularly relevant in gills. ANL elicited alterations in central neurotransmission affecting ventilation coupled with very low levels of oxidative damage in gills. Results indicate chronic toxicity data are determinant to improve HNS hazard assessment if the aim is to obtain reliable risk calculations, and develop effective predictive models avoiding overestimation but sufficiently protective. Accounting for multibiomarker interactions brought otherwise overlooked information about C. maenas responses and MoA of ACN and ANL.
Differential protection of pre- versus post-treatment with curcumin, Trolox, and N-acetylcysteine against acrylonitrile-induced cytotoxicity in primary rat astrocytes
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Acrylonitrile (AN) is an extensively manufactured aliphatic nitrile used in the synthesis of acrylic fiber, resins and plastics and in the manufacture of soft prosthesis material, highly permeable dialysis tubing and medical gloves (IARC, 1999). Although the nervous system response to acute AN exposure exhibits characteristics analogous to acute cyanide poisoning, the exact mechanism(s) of AN-induced neurotoxicity has yet to be fully defined (Enongene et al., 2000; Ghanayem et al., 1991). Oxidative stress may be involved in AN-induced neurotoxicity secondary to depletion of antioxidants and/or increased production of reactive oxygen species (ROS).
This study was designed to examine the differential protection of pre- versus post-treatment with three different antioxidants, curcumin (CUR), Trolox, and N-acetylcysteine (NAC), on acrylonitrile (AN)-induced cytotoxicity in primary rat astrocytes.
Primary astrocyte cultures were treated with CUR, Trolox and NAC for 4 h prior to, or following 24 h treatment with AN (2.5 mM). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) release, lipid peroxidation, glutathione, reactive oxygen species (ROS) and mitochondrial membrane potential were measured to evaluate protection associated with the three antioxidants. Knockdown of Nrf2 expression by liposome transfection with siRNA was used to confirm the role of Nrf2 activation in the protection associated with the three antioxidants.
Compared with AN treatment alone, pre-treatment with CUR at either concentration significantly increased cell viability and mitochondrial membrane potential, and reduced glutathione levels; lipid peroxidation and ROS production were significantly decreased as well. NAC also showed significant efficacy in attenuating AN-induced toxicity at higher concentration. However, pre-treatment with Trolox failed to ameliorate the AN-induced toxicity. When post-treatment with Trolox, this antioxidant led to significant protective effects at both concentrations, while CUR and NAC were efficacious only at the higher concentrations. Knockdown of Nrf2 only abolished the protective effects of CUR pre-treatment on AN-induced cytotoxicity, while the protective effects of NAC and Trolox pre-treatment groups showed no differences between the Nrf2-knockdown and non-knockdown treatments.
The selected antioxidants exert differential cellular protection when administered prior or subsequent to AN-induced cytotoxic events in decreasing cellular viability, antioxidative capacity and mitochondrial function, enhanced cytotoxicity and ROS production. These results suggest that antioxidants should be carefully chosen for their efficacy in preventing or diminishing oxidative damage caused by AN. The differential effect of pre- and post-treatment may be attributed to activation of the Nrf2 signaling pathway.
Simulation of a hazardous and noxious substances (HNS) spill in the marine environment: Lethal and sublethal effects of acrylonitrile to the european seabass
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Fish from the 2 mg L−1 acrylonitrile exposure presented the skin extremely dark and impairment of swimming performance, characterized by low swimming activity with uncontrolled circular movements at the top of the aquarium, together with bumps with the aquarium walls. The swimming performance observed in fish at the highest acrylonitrile exposure dose, suggest an impact in the nervous system, which integrates well with the observations in mammals (Ghanayem et al., 1991; Gagnaire et al., 1998; Esmat et al., 2007). However, understanding the mechanisms underlying a potential effect on fish nervous system requires further investigation through the measurement of neurotoxic parameters such as cholinesterase activity in fish brain.
Despite the extensive maritime transportation of Hazardous and Noxious Substances (HNS), there is a current lack of knowledge on the effects posed by HNS spills on the marine biota. Among the HNS identified as priority, acrylonitrile was selected to conduct ecotoxicological assays. We assessed the acute and subletal effects of acrylonitrile in seabass, followed by a recovery phase to simulate the conditions of a spill incident. The work aimed at testing a broad range of biological responses induced by acrylonitrile. Sublethal exposure to the highest two doses increased the fish mortality rate (8.3% and 25% mortality in 0.75 and 2 mg L⁻¹ acrylonitrile concentrations), whereas no mortality were observed in control and 0.15 mg L⁻¹ treatments. Additionally, important alterations at sub-individual level were observed. Acrylonitrile significantly induced the activities of Catalase– CAT and Glutathione S-Transferase – GST; and the levels of DNA damage were significantly increased. Conversely, Superoxide Dismutase– SOD – activity was found to be significantly inhibited and no effects were found on Lipid Peroxidation– LPO and ethoxyresorufin O-deethylase – EROD – activity. Following a 7 d recovery period, the levels of CAT, GST and EROD fell to levels at or below those in the control. In the 2 mg L⁻¹ group, SOD remained at the levels found during exposure phase. This study has gathered essential information on the acute and subletal toxicity of acrylonitrile to seabass. It also demonstrated that 7 d recovery allowed a return of most endpoints to background levels. These data will be useful to assist relevant bodies in preparedness and response to HNS spills.
Elevation of 4-hydroxynonenal and malondialdehyde modified protein levels in cerebral cortex with cognitive dysfunction in rats exposed to 1-bromopropane
2013, Toxicology
Citation Excerpt :
In principle and where possible, the administration route in animal experiments should be relevant to anticipated human exposure. As one of the most convenient and accurate route of administration (Andersen, 2003; Perera et al., 1989), gavage had also been employed in the studies of 1-BP (Lee et al., 2005, 2010) and other volatile neurotoxicants such as ethylbenzene (Mellert et al., 2007), acrylonitrile (Ghanayem et al., 1991), styrene (Chakrabarti, 2000) and BDE-99 (Bellés et al., 2010). However the rats exposed to 1-BP by gavage exhibited similar neurotoxic symptoms observed in human cases.
1-Bromopropane (1-BP), an alternative to ozone-depleting solvents (ODS), exhibits central nervous system (CNS) toxicity in animals and humans. This study was designed to relate CNS damage by Morris water maze (MWM) test and oxidative stress to 1-BP exposure in the rat. Male Wistar rats were randomly divided into 4 groups (n = 10), and treated with 0, 200, 400 and 800 mg/kg bw 1-BP for consecutive 12 days, respectively. From day 8 to day 12 of the experiment, MWM test was employed to assess the cognitive function of rats. The cerebral cortex of rats was obtained immediately following the 24 h after MWM test conclusion. Glutathione (GSH), oxidized glutathione (GSSG) and total thiol (total-SH) content, GSH reductase (GR) and GSH peroxidase (GSH-Px) activities, malondialdehyde (MDA) level, as well as 4-hydroxynonenal (4-HNE) and MDA modified proteins in homogenates of cerebral cortex were measured. The obtained results showed that 1-BP led to cognitive dysfunction of rats, which was evidenced by delayed escape latency time and swimming distances in MWM performance. GSH and total-SH content, GSH/GSSG ratio, GR activity significantly decreased in cerebral cortex of rats, coupling with the increase of MDA level. 4-HNE and MDA modified protein levels obviously elevated after 1-BP exposure. GSH-Px activities in cerebral cortex of rats also increased. These data suggested that 1-BP resulted in enhanced lipid peroxidation of brain, which might play an important role in CNS damage induced by 1-BP.
Curcumin pretreatment protects against acute acrylonitrile-induced oxidative damage in rats
2010, Toxicology
Acrylonitrile (AN) is widely used in the manufacturing of fibers, plastics and pharmaceuticals. Free radical-mediated lipid peroxidation is implicated in the toxicity of AN. The present study was designed to examine the ability of curcumin, a natural polyphenolic compound, to attenuate acute AN-induced lipid peroxidation in the brain and liver of rats. Male Sprague–Dawley rats were orally administered curcumin at doses of 0 (olive oil control), 50 or 100 mg/kg bodyweight daily for 7 consecutive days. Two hours after the last dose of curcumin, rats received an intraperitoneal injection of 50 mg AN/kg bodyweight. Acute exposure to AN significantly increased the generation of lipid peroxidation products, reflected by high levels of malondialdehyde (MDA) both in the brain and liver. These increases were accompanied by a significant decrease in reduced glutathione (GSH) content and a significant reduction in catalase (CAT) activity in the same tissues. No consistent changes in superoxide dismutase (SOD) activity were observed between the control and AN-treatment groups in both tissues. Pretreatment with curcumin reversed the AN-induced effects, reducing the levels of MDA and enhancing CAT activity and increasing reduced GSH content both in the brain and liver. Furthermore, curcumin effectively prevented AN-induced decrease in cytochrome c oxidase activity in both liver and brain. These results establish that curcumin pretreatment has a beneficial role in mitigating AN-induced oxidative stress both in the brains and livers of exposed rats and these effects are mediated independently of cytochrome P450 2E1 inhibition. Accordingly, curcumin should be considered as a potential safe and effective approach in attenuating the adverse effects produced by AN-related toxicants.
Toxicity and oxidative stress of acrylonitrile in rat primary glial cells: Preventive effects of N-acetylcysteine
2007, Toxicology Letters
Brain is a target organ for acrylonitrile (ACN) toxicity. The objective of the current work was to investigate ACN cytotoxicity in rat primary glial cells, using N-acetyl-l-cysteine (NAC) as a potential protective agent. Cells were exposed in vitro to different concentrations of ACN for different time intervals. Cell membrane integrity was assessed by trypan blue exclusion and lactate dehydrogenase (LDH) leakage. Approximately 50% membrane damage was observed in the incubations containing 1.0 mM ACN for 3 h. Therefore, these experimental conditions were used in subsequent studies. ACN enhanced lipid peroxidation, as indicated by malondialdehyde (MDA) accumulation, and depleted reduced glutathione (GSH) level with no change in total glutathione. Also, ACN was activated to cyanide (CN⁻) with dramatic decrease in ATP level. Cell treatment with NAC prior to exposure to ACN afforded some protection; as indicated by reducing MDA level and elevating level of both reduced and total glutathione. Further, pretreatment with NAC inhibited CN⁻ formation and caused an increase in ATP level. Our results indicate that ACN is toxic to rat primary glial cells as evidenced by induction of oxidative stress and generation of CN⁻ with subsequent energy depletion. NAC can play an important role against ACN-induced oxidative damage.

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¹: Present address: NIH/NIEHS, RTP, NC.

²: Present address: Department of Biology, University of Texas Pan American, Edinburg, TX.

³: Present address: Cairo, Egypt.

⁴: Present address: U.S. EPA, Cincinnati, OH.

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Assessment of the acute acrylonitrile-induced neurotoxicity in rats

Abstract

Studies on the mechanism of acrylonitrile neurotoxicity

Toxicol. Appl. Pharmacol.

Acrylonitrile in vivo metabolism in rats and mice

Drug Metab. Dispos.

Influence of sulfhydryls reagents and heavy metals on the functional state of the muscarinic acetylcholine receptors in rat brain

Mol. Pharmacol.

Primary brain tumors in Fischer 344 rats chronically exposed to acrylonitrile in drinking water

Food Chem. Toxicol.

Toxicity of acrylonitrile (vinyl cyanide) I. A study of the acute toxicity

J. Ind. Hyg. Toxicol.

Regulation of muscarinic receptor binding of guanine nucleotides and N-ethylmaleimide

J. Supramol. Struct.

Effect of acute acrylonitrile exposure on metrazol induced seizures in the rat

Neurotoxicology

Molecular interactions of acrylonitrile and potassium cyanide with rat blood

Chem. Biol. Interact.

Hemoglobin degradation, lipid peroxidation and inhibition of Na+/K+-ATPase in rat erythrocytes exposed to acrylonitrile

J. Biochem. Toxicol.

Metabolism of acrylonitrile by isolated rat hepatocytes

Cancer Res.

In vivo biotransformation and biliary excretion of 1-14C acrylonitrile in rats

Arch. Toxicol.

Hemoglobin degradation, lipid peroxidation and inhibition of Na⁺/K⁺-ATPase in rat erythrocytes exposed to acrylonitrile

In vivo biotransformation and biliary excretion of 1-¹⁴C acrylonitrile in rats