Neuropathological Evaluation of Acrylamide- and 3,3'-Iminodipropionitrile-Induced Neurotoxicity in a Rat 28-Day Oral Toxicity Study-Collaborative Project for Standardization of Test Procedures and Evaluation of Neurotoxicity.

Abstract

Abstract:In order to standardize test procedures for evaluation of neurotoxicity of chemical exposure, a collaborative study with a common protocol based on the Organization for Economic Cooperation and Development (OECD) test guideline TG407 was conducted by eleven laboratories, using acrylamide and 3,3'-iminodipropionitrile (IDPN) as positive neurotoxicants. This report summarizes the results of this neuropathological evaluation of neurotoxicity, when acrylamide (3, 10, and 30 mg/kg) and IDPN (20, 50, and 100 mg/kg) were orally administered to rats for 28 days. The study revealed typical alterations, including degeneration of peripheral nerve fibers and Purkinje's cell necrosis with acrylamide, and axonal swelling in the brainstem and spinal cord with IDPN. In addition to the neurotoxicity, IDPN exerted toxic effects on the cerebral arteries, hyalinization of vessel walls being observed. In general, the neuropathological findings well demonstrated the neurotoxicity of both chemicals. These results indicate that neuropathological evaluation can play a crucial role in screening for potential neurotoxicants with risk for human health, the expected neurotoxic effects being detected in this collaborative study consistently in all the laboratories. (J Toxicol Pathol 2001; 14: 279-287)

Alteration of microRNA expressions in the pons and medulla in rats after 3,3′-iminodipropionitrile administration

“…Abnormal behaviors and decreased auditory response might be associated with IDPN-induced vestibular and auditory hair cell injuries, as reported in some studies 2 , 37 , 38 , 39 , 40 , although the possibility that decreased auditory response might be caused by weakened condition in animals could not be ruled out. In contrast to our result, it has been reported that IDPN induced sciatic nerve degeneration after 28-day (at 100 mg/kg) or 5-week (at 125 mg/kg) oral administration 5 , 7 . Since the observation period in our study was shorter than that of the reported studies, no sciatic nerve degeneration was detected in the present study.…”

“…The nervous symptoms and histopathological changes in the present study are in general agreement with some reports on the features of IDPN-induced neurotoxicity 1 , 3 , 4 , 6 , 7 , 36 . Abnormal behaviors and decreased auditory response might be associated with IDPN-induced vestibular and auditory hair cell injuries, as reported in some studies 2 , 37 , 38 , 39 , 40 , although the possibility that decreased auditory response might be caused by weakened condition in animals could not be ruled out.…”

“…The behavioral manifestation referred to as “waltzing syndrome,” which includes circling, repetitive head movements, and hyperactivity, has been reported in IDPN-treated rodents 1 , 2 , 3 . The neurotoxic effects caused by IDPN include proximal axonal neuropathy in the nervous system characterized by accumulation of neurofilaments 4 , 5 , 6 , 7 . Although IDPN has been widely used in neurotoxic models, its mechanism for brain impairment has not been fully understood.…”

Vascular Lesion in the Meninx and Retina Following Administration of 3,3'-Iminodipropionitrile (IDPN) in Rats

“…The dosage level of IDPN was established according to the results of the previously mentioned collaborative neurotoxicity study. In the collaborative study, vascular lesions in the brain and spinal cord were seen in 6 of 11 laboratories, however, there were no dead or moribund rats at treatments of 100 mg/kg IDPN per day 10 . Therefore, a dosage slightly higher than that of the collaborative study was selected for the present study in order to be more certain of inducing the vascular lesions.…”

“…A collaborative neurotoxicity study using IDPN with a common protocol based on the Organization for Economic Cooperation and Development (OECD) test guideline TG407 was conducted by 11 laboratories in Japan 10 . In the histopathological examination of this study, which was restricted to the central and peripheral nervous systems, we identified angitis or hyalinization of the vascular wall in the meninx of rats receiving 100 mg/kg of IDPN for 28 days.…”