The Ototoxic Effects Induced in Rats by Treatment for 12 Weeks with 2‐Butenenitrile, 3‐Butenenitrile and cis‐2‐Pentenenitrile

Abstract

Brainstem auditory and visual evoked-potentials were studied in male Sprague-Dawley rats during subchronic oral treatment with three unsaturated aliphatic nitriles. The rats were given, by gastric intubation, doses of 10, 20 and 40 mg ¡ kg ª1 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg ¡ kg ª1 of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Rats in the high dosage groups exhibited a complete disappearance of the five waves of the auditory evoked-potentials. There was a decrease in the amplitudes of the 2nd component of the auditory evoked-potentials. Those changes were not reversible at the 8th week of the recovery period. A dose-dependent effect on inner and outer hair cells was observed in the organ of Corti. The basal part of the cochlea was the most affected. Though no measurements were made of systemic exposure, a tentative ranking of decreasing ototoxicity of these three unsaturated nitriles might be proposed based on the electrophysiological deficiencies and histological losses observed: 3-butenenitrile Ͼcis-2-pentenenitrile Ͼcis/trans-2-butenenitrile. Moreover, rats treated with those nitriles showed a corneal opacity as well as a decrease in the amplitude and lengthening of the peak latencies of the visual evoked-potentials. These latter changes were reversible by the end of the 8th week of the recovery period and appeared to be related to the opacity of the cornea.

Reduced Systemic Toxicity and Preserved Vestibular Toxicity Following Co-treatment with Nitriles and CYP2E1 Inhibitors: a Mouse Model for Hair Cell Loss

“…In the present study, we did not assess the effect of cis-crotononitrile and allylnitrile on the auditory system. However, in the rat, both nitriles have been demonstrated to cause hearing loss and cochlear hair cell degeneration (Gagnaire et al 2001;Balbuena andLlorens 2001, 2003), with similar dose-response relationships between cochlear and vestibular damage. Further studies are required to assess whether the present exposure models result in useful cochlear damage in addition to the assessed vestibular damage.…”

“…standing need in inner ear research, for example, in studies to develop strategies for alleviating human labyrinth damage by hair cell protection, regeneration, or replacement. One possible model is exposure to the nitriles allylnitrile and cis-crotononitrile, with a known ototoxic potential (Balbuena andLlorens 2001, 2003;Gagnaire et al 2001;Soler-Martín et al 2007;Boadas-Vaello et al 2007Saldaña-Ruíz et al 2012a). In this study, we have evaluated refining these models through the use of pharmacological agents that inhibit the CYP2E1 enzyme to reduce the acute systemic toxicity of the nitriles.…”

“…Hair cell loss has been found in the vestibular and auditory epithelia of rats and mice after exposure to 3,3′-iminodipropionitrile (IDPN) (Llorens et al 1993;Llorens and Demêmes 1994;Crofton et al 1994), allylnitrile (Balbuena and Llorens 2001;Gagnaire et al 2001), crotononitrile (Gagnaire et al 2001;Llorens et al 1998), and cis-2-pentenenitrile (Gagnaire et al 2001;Saldaña-Ruíz et al 2012a, b). In the case of crotononitrile, only the cisisomer is ototoxic in rats and mice (Balbuena and Llorens 2003;Soler-Martín et al 2007), while transcrotononitrile is ototoxic at sublethal levels in mice (Saldaña-Ruíz et al 2012a) but not in rats (BoadasVaello et al 2005).…”

Strategies and tools for preventing neurotoxicity: To test, to predict and how to do it

“…Many nitriles are known to cause acute toxicity through cyanide release by xenobiotic metabolism enzymes, a toxic endpoint already addressed by some modeling studies (Grogan et al, 1992). The work by several groups, including ours, has demonstrated that several nitriles cause a variety of neurotoxic effects, such as degeneration of specific populations of neurons in the central nervous system (Boadas-Vaello et al, 2005;Seoane et al, 2005) and degeneration of sensory systems including the olfactory (Genter et al, 1992), auditory (Gagnaire et al, 2001) and vestibular systems (Llorens et al, 1993;Llorens, 2001, 2003). We have observed that vestibular toxicity is not related to cyanide release (Boadas-Vaello et al, 2007) and is associated with strict structural requirements (Balbuena and Llorens, 2003) that may depend on the animal species, as the case of trans-crotononitrile, which causes neuronal degeneration in the rat (Boadas-Vaello et al, 2005;Seoane et al, 2005) and vestibular toxicity in the mouse (Saldaña-Ruíz et al, 2012).…”

Vestibular toxicity of cis-2-pentenenitrile in the rat

“…Among sensory systems, the inner ear is a major target for several nitriles: degeneration of the vestibular and/or auditory sensory hair cells has been reported in rodents exposed to 3,3'-iminodipropionitrile (IDPN) (Llorens et al, 1993;Llorens and Demêmes, 1994;Crofton et al, 1994;Soler-Martín et al, 2007), allylnitrile (Balbuena and Llorens, 2001;Gagnaire et al, 2001), racemic crotononitrile (Llorens et al, 1998;Gagnaire et al, 2001), and cis-crotononitrile (Balbuena and Llorens, 2003). IDPN has also been shown to cause vestibular toxicity in frogs (Soler-Martin et al, 2007).…”