Developmental neurotoxicity following neonatal exposure to 3,3′-iminodipropionitrile in the rat

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Adult exposure to the neurotoxicant 3,3′-iminodipropionitrile (IDPN), induces a hyperkinetic syndrome consisting of spontaneous head movements, abnormal circling, backward locomotion, and sensory disruption. We report here the behavioral effects of developmental exposure to IDPN in the rat. Animals were exposed (IP) to either saline, 75, 150, or 300 mg/kg/day on postnatal days (PND) 5–7. Animals were tested for: Figure-8 maze activity (PND 13–60); olfactory discrimination learning (PND 18 & 24); T-maze alternation and position discrimination learning (PND 25 & 26); acoustic startle response (PND 23, 61, & 62); passive avoidance (PND 70). To better define the dose response, a separate group of animals was exposed to either saline or 225 mg/kg/day (PND 5–7) and tested in the activity, T-maze, and startle paradigms. Animals exposed to 225 mg/kg/day and 300 mg/kg/day had decreased weight gain and lethality was 25% in the latter group. Signs of the IDPN syndrome, evident in the 225 and 300 mg/kg/day groups, persisted throughout the course of the study. IDPN exposed animals (300 mg/kg/day) were hyperactive on PND 17–60, failing to develop habituation in the Figure-eight maze until PND 60. The acoustic startle response was depressed for the 225 and 300 mg/kg/day groups on PND 23 only. Auditory thresholds were elevated for a high-frequency (40 kHz) but not a low-frequency tone (5 kHz) for the 225 and 300 mg/kg/day groups, indicating a hearing loss. IDPN treatment also disrupted performance of olfactory discrimination learning and produced cognitive deficits in T-maze learning in infants (300 mg/kg/day). That cognitive deficits also appeared in adulthood (PND 70) was demonstrated by learning deficits in a passive avoidance task at 150 and 300 mg/kg/day. IDPN (300 mg/kg/day) also caused a decrease in the wet weight of the whole brain (8%) and the cerebellum (12%) but not the hippocampus. These data demonstrate that short-term, neonatal exposure to IDPN in the rat produced persistent alterations in sensory, motor, and cognitive aspects of nervous system function.