Vestibular toxicity of cis-2-pentenenitrile in the rat

Saldaña-Ruíz, Sandra; Hernández-Mir, Gerard; Sedó-Cabezón, Lara; Cutillas, Blanca; Llorens, Jordi

doi:10.1016/j.toxlet.2012.04.010

Cited by 11 publications

(10 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, this model may be useful to identify the cellular and molecular basis of vestibular dysfunction and recovery associated with chronic ototoxicity and washout. Although the literature contains a noticeable number of references on the CNS toxicity of IDPN ( Wang et al, 2015 ), their value is dubious as they ignore the firmly established fact that the effects of IDPN on spontaneous motor behavior are a syndrome of vestibular dysfunction ( Llorens et al, 1993 ; Llorens and Rodríguez-Farré, 1997 ; Boadas-Vaello et al, 2005 ; Soler-Martín et al, 2007 ; Saldaña-Ruíz et al, 2012a , b ). The test battery used in the present study to assess vestibular dysfunction is highly specific and not affected by the alleged CNS effects of IDPN ( Llorens and Rodríguez-Farré, 1997 ; Seoane et al, 1999 ; Boadas-Vaello et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

“…One cause of vestibular dysfunction is inner ear damage following exposure to ototoxic chemicals. These include therapeutic drugs, such as aminoglycoside antibiotics and the chemotherapeutic agent cisplatin, as well as a number of workplace chemicals and environmental pollutants ( Forge and Schacht, 2000 ; Sergi et al, 2003 ; Hodgkinson and Prasher, 2006 ; Schacht et al, 2012 ; Saldaña-Ruíz et al, 2012a , b ; Sedó-Cabezón et al, 2014 ). A well-established result of ototoxic insult is the loss of the sensory hair cells (HCs) responsible for mechanotransduction in both the vestibular and auditory systems.…”

Section: Introductionmentioning

confidence: 99%

“…Like the antibiotics, nitriles also show the characteristic intra-epithelial and inter-epithelial differences in susceptibility: hair cell loss progresses in a basal to apical order in the cochlea; in a central to peripheral order within each vestibular epithelia; and in a crista to utricle to saccule order across the vestibular epithelia (Llorens et al, 1993; Llorens and Demêmes, 1994 ; Balbuena and Llorens, 2001 , 2003 ; Soler-Martín et al, 2007 ). Humans can be exposed to natural ( Tanii et al, 2004 ) and industrial ( Saldaña-Ruíz et al, 2012a ) ototoxic nitriles, but clinical evidence of their ototoxicity is not available. Also, the mechanisms involved in their ototoxicity remain unexplored, so it is feasible that many differences exist within those mechanisms identified for aminoglycosides and cisplatin ( Schacht et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats.

Sedó-Cabezón

Jedynak

Boadas-Vaello

et al. 2015

Disease Models &Amp; Mechanisms

Self Cite

View full text Add to dashboard Cite

Ototoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs). However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3′-iminodipropionitrile (IDPN). Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI) and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents) and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats.

Sedó-Cabezón

Jedynak

Boadas-Vaello

et al. 2015

Disease Models &Amp; Mechanisms

Self Cite

View full text Add to dashboard Cite

show abstract

“…While cis-crotononitrile caused behavioral effects and vestibular hair cell loss (1-3, 2-4, and 3-5 vestibular ratings as compared with control ( 0-1 ratings ) in both rats 11 ) ( 80, 100, and 120 mg / kg / day, for 3 days ) and mice 20) , trans-crotononitrile (250 mg/kg/day, for 3 days) caused rearing deficits with no vestibular dysfunction or hair cell loss 11) , but caused the same behavioral syndrome and hair cell loss in mice 20) . Rats receiving 1.5, 1.75, and 2.0 mmol / kg of cis-2-pentenenitrile displayed reduced rearing activity in the open field and increased rating scores on the vestibular dysfunction test battery as well as hair cell loss (1-3, 1-4, and 3-4 vestibular ratings as compared with control (0-1) 12) . Dose-response studies on allyl showed the match between behavioral effects and hair cell loss in mice 21) .…”

Section: Toxicitymentioning

confidence: 93%

“…A significant correlation has been shown between acute toxicity and the octanol/water partition coefficient for nitriles, including allyl nitrile 7) . Rodents administered allyl nitrile at high doses exhibited behavioral abnormalities 8) ; this is not known to occur with other mononitriles, with the exception of crotononitrile and 2-pentenenitrile [9][10][11][12] . The dinitrile 18) Fos induction in the brain of mice after allyl nitrile administration…”

Section: Toxicitymentioning

confidence: 99%

Allyl nitrile: Toxicity and health effects

Tanii

2017

Journal of Occupational Health

View full text Add to dashboard Cite

Objectives: Allyl nitrile ( 3-butenenitrile ) occurs naturally in the environment, in particular, in cruciferous vegetables, indicating a possible daily intake of the compound. There is no report on actual health effects of allyl nitrile in humans, although it is possible that individuals in the environment are at a risk of exposure to allyl nitrile. However, little is known about its quantitative assessment for the environment and bioactivity in the body. This study provides a review of previous accumulated studies on allyl nitrile. Methods: Published literature on allyl nitrile was examined for findings on toxicity, metabolism, risk of various cancers, generation, intake estimates, and low-dose effects in the body. Results : High doses of allyl nitrile produce toxicity characterized by behavioral abnormalities, which are considered to be produced by an active metabolite, 3,4-epoxybutyronitrile. Cruciferous vegetables have been shown to have a potential role in reducing various cancers. Hydrolysis of the glucosinolate sinigrin, rich in cruciferous vegetables, results in the generation of allyl nitrile. An intake of allyl nitrile is estimated at 0.12 μmol/kg body weight in Japan. Repeated exposure to low doses of allyl nitrile upregulates antioxidant/phase II enzymes in various tissues ; this may contribute to a reduction in neurotoxicity and skin inflammation. These high and low doses are far more than the intake estimate. Conclusion: Allyl nitrile in the environment is a compound with diverse bioactivities in the body, characterized by inducing behavioral abnormalities at high doses and some antioxidant/phase II enzymes at low doses.

show abstract

Calyx junction dismantlement and synaptic uncoupling precede hair cell extrusion in the vestibular sensory epithelium during sub-chronic 3,3′-iminodipropionitrile ototoxicity in the mouse

et al. 2018

Self Cite

View full text Add to dashboard Cite

The cellular and molecular events that precede hair cell (HC) loss in the vestibular epithelium during chronic ototoxic exposure have not been widely studied. To select a study model, we compared the effects of sub-chronic exposure to different concentrations of 3,3'iminodipropionitrile (IDPN) in the drinking water of two strains of mice and of both sexes. In subsequent experiments, male 129S1/SvImJ mice were exposed to 30 mM IDPN for 5 or 8 weeks; animals were euthanized at the end of the exposure or after a washout period of 13 weeks. In behavioral tests, IDPN mice showed progressive vestibular dysfunction followed by recovery during washout. In severely affected animals, light and electron microscopy observations of the vestibular epithelia revealed HC extrusion towards the endolymphatic cavity. Comparison of functional and ultrastructural data indicated that animals with fully reversible dysfunction did not have significant HC loss or stereociliary damage, but reversible dismantlement of the calyceal junctions that characterize the contact between type I HCs (HCI) and their calyx afferents. Immunofluorescent analysis revealed the loss of calyx junction proteins, caspr1 and tenascin-C, during exposure and their recovery during washout. Synaptic uncoupling was also recorded, with loss of pre-synaptic Ribeye and post-synaptic GluA2 puncta, and differential reversibility among the three different kinds of synaptic contacts existing in the epithelium. qRT-PCR analyses demonstrated that some of these changes are at least in part explained by gene expression modifications. We concluded that calyx junction dismantlement and synaptic uncoupling are early events in the mouse vestibular sensory epithelium during sub-chronic IDPN ototoxicity.

show abstract

Vestibular toxicity of cis-2-pentenenitrile in the rat

Cited by 11 publications

References 31 publications

Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats.

Transient alteration of the vestibular calyceal junction and synapse in response to chronic ototoxic insult in rats.

Allyl nitrile: Toxicity and health effects

Calyx junction dismantlement and synaptic uncoupling precede hair cell extrusion in the vestibular sensory epithelium during sub-chronic 3,3′-iminodipropionitrile ototoxicity in the mouse

Contact Info

Product

Resources

About