Neurovestibular Toxicities of Acrylonitrile and Iminodipropionitrile in Rats: A Comparative Evaluation of Putative Mechanisms and Target Sites

Abstract

This investigation was aimed to study the effects of individual and concomitant exposures of the two nitrile compounds, the industrially important acrylonitrile (ACN; 5, 15, 45 mg/kg/day) and the positive control iminodipropionitrile (IDPN; 100 mg/kg/day) in rats. The six treatment groups were 1 (control), 2 (ACN 5), 3 (ACN 15), 4 (ACN 45), 5 (IDPN), and 6 (IDPN + ACN 15). Both the drugs were started on the same day and continued for 9 days (IDPN was given daily 30 min before ACN but stopped a day earlier). The animals were daily observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, and contact inhibition of righting reflex. There was no dyskinetic behavioral abnormality in the animals treated with any of the three doses of ACN whereas all the rats in IDPN alone treated group developed clear symptoms of excitation, circling, and chorea syndrome (ECC syndrome) on day 9. Concomitant treatment of rats with ACN significantly attenuated the severity of IDPN-induced behavioral deficits. Administration of ACN significantly depleted glutathione (GSH) in striatum, hippocampus and cerebral cortex; IDPN significantly reduced the GSH only in striatum. The anterior striatum showed intense tyrosine hydroxylase (TH) expression in IDPN alone treated rat as compared to control and ACN alone treated rat. Cotreatment with ACN reduced the intensity of TH immunostaining in IDPN-treated rats. Administration of IDPN alone caused massive loss of vestibular sensory hair cells in the crista ampullaris whereas the sensory epithelium appeared intact in ACN alone treated groups. The animals receiving the combination of ACN and IDPN showed comparatively less degeneration of sensory hair cells than IDPN alone group. These findings suggest that ACN and IDPN produce different behavioral effects that are exerted through entirely different mechanisms; the nervous and vestibular systems appear to be the major target sites of these toxins, respectively.