Learning and memory deficits in rats following exposure to 3,3′-iminodipropionitrile

Peele, David B.; Allison, S.D.; Crofton, Kevin M.

doi:10.1016/0041-008x(90)90193-x

Cited by 29 publications

(16 citation statements)

References 23 publications

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“…Only a few olfactory toxicants have previously been assessed for behavioural changes; these include 3-methylindole, IDPN, dichlobenil and methimazole, (Peele et al 1990(Peele et al , 1991Llorens et al 1994;Genter et al 1996). The results of these studies indicate that some behavioural alterations may be attributable to defective olfactory function.…”

Section: Introductionmentioning

confidence: 94%

Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice

Carlsson

Bahrami

Fredriksson

et al. 2002

Archives of Toxicology

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Methylsulphonyl-2,6-dichlorobenzene [2,6-(diCl-MeSO(2)-B)], and its 2,5-chlorinated isomer [2,5-(diCl-MeSO(2)-B)] bind firmly in the olfactory mucosa of mice. Both isomers are also selectively localised in the olfactory bulb. Persistent olfactory mucosal metaplasia is induced by 2,6-(diCl-MeSO(2)-B) whereas 2,5-(diCl-MeSO(2)-B) has no effects. Furthermore, a strong induction of glial fibrillary acidic protein (GFAP) restricted to the olfactory bulb has been reported in 2,6-(diCl-MeSO(2)-B)-treated mice. To explore whether these lesions give rise to early or long-lasting changes in behaviour, spontaneous motor activity and radial arm maze (RAM) learning were examined at 1, 2, 4 and 12 weeks following an intraperitoneal injection of a single low (32 mg/kg) or high (65 mg/kg) dose of 2,6-(diCl-MeSO(2)-B). 2,5-(DiCl-MeSO(2)-B) (65 mg/kg) was used as a negative control. Hyperactivity was observed in all treatment groups while deficits in the RAM performance was only seen in the 2,6-(diCl-MeSO(2)-B)-treated groups. Alterations in motor activity and impaired performance in the RAM-test induced by 2,6-(diCl-MeSO(2)-B) persisted up to 2 weeks in the low-dose group and 12 weeks in the high-dose group. The low-dose group consistently showed a less pronounced effect than the high-dose group. The 2,5-(diCl-MeSO(2)-B)-induced changes in motor activity declined rapidly and did not remain after 2 weeks. As determined by immunohistochemistry, 2,6-(diCl-MeSO(2)-B)-induced GFAP immunoreactivity was mainly confined to the glomerular layer of the olfactory bulb. We propose that the behavioural deficits caused by 2,6-(diCl-MeSO(2)-B) result from a primary loss of sensory neurons in the olfactory mucosa with consequent astrocyte proliferation in the glomerular layer of the olfactory bulb. A targeted uptake of metabolites into the olfactory bulb could also contribute to the GFAP induction and/or behaviour response.

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Section: Introductionmentioning

confidence: 94%

Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice

Carlsson

Bahrami

Fredriksson

et al. 2002

Archives of Toxicology

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“…Some of them, including 3,3'iminodipropionitrile or P-dimethylaminopropionitrile, show striking central and peripheral neurotoxic properties, (Hartmann et a/. 1985;Lowndes et al 1985;O'Donoghue 1985;Peele et a/. 1990;Llorens & Rodriguez-Farrt.…”

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confidence: 99%

Electrophysiological Deficiency in Peripheral Nerve Induced by Treatment for 12 Weeks with 2‐Butenenitrile, 3‐Butenenitrile, cis‐2‐Pentenenitrile and 3, 3′‐Iminodipropionitrile in Rats

Gagnaire

Marignac

1999

Pharmacology & Toxicology

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Motor and sensory conduction velocities and amplitudes of the sensory and motor action potentials of the tail nerve 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-' 3-butenenitrile (ally1 cyanide) and 25, 50 and 100 mg . kg-' of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Moreover, 3,3'-iminodipropionitrile was administered likewise at doses of 25, 50 and 100 mg . kg-' as reference neurotoxicant. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Moreover, rats exhibited both time-and concentration-dependent decreases in motor and sensory conduction velocities and amplitudes of the sensory action potentials. Nerve conduction velocities were partially reversible after 8 weeks of recovery. Rats receiving 3,3'-iminodipropionitrile developed deafness, head weaving and significant irreversive deficiencies in all the electrophysiological parameters studied. Further toxicological studies with related unsaturated nitriles should be carried out to determine the potential importance of the cis/trans isomerism in the observed neurotoxicity.

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“…Four daily doses of MMI were more effective than two daily doses in reducing the severity of a 1000 mg/kg dose of IDPN. MMI also partially blocked the body weight loss normally observed after acute exposures to IDPN (Peele et al, 1990;Crofton and Knight, 1991;Crofton et al, 1996). The reason for small decreases in body weight in the MMI4 group is currently unknown.…”

Section: Discussionmentioning

confidence: 91%

Effect of Methimazole, an FMO Substrate and Competitive Inhibitor, on the Neurotoxicity of 3,3′-Iminodipropionitrile in Male Rats

et al. 1997

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This study was designed to examine the role of flavin-containing monooxygenase (FMO) on the auditory and vestibular neurotoxicity of 3,3'-iminodipropionitrile (IDPN) using the FMO substrate and competitive inhibitor methimazole (MMI). Specifically, the purpose was to block the FMO-mediated conversion of IDPN to the putative neurotoxic metabolite N-hydroxy3,3'-iminodipropionitrile (HOIDPN). In three separate experiments, adult male Long-Evans hooded rats were administered (ip) saline (vehicle), MMI, IDPN, or HOIDPN individually, or a combination of IDPN and MMI or HOIDPN and MMI. Animals were observed daily for signs of the ECC syndrome (excitation with choreiform and circling movements) for 10 days. One to 2 weeks after exposure, a battery of behavioral tests was used to examine vestibular and auditory function. MMI completely blocked the neurotoxicity associated with a 600 mg/kg dose of IDPN and partially blocked the effects of a 1000 mg/kg dose of IDPN. In contrast, MMI failed to block, and instead increased, the neurotoxicity associated with HOIDPN. These data suggest that FMOmediated metabolism of IDPN is necessary for the generation of a metabolite responsible for the vestibular and auditory neurotox- icitieS. C 1997 Society of ToThe synthetic organonitrile 3,3'-iminodipropionitrile (IDPN) is known to produce the ECC syndrome excitation with cho-' This article has been reviewed by the National Health Effects and Environmental Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This work was supported in part by the North Carolina Agricultural Research Service (M.B.G.), NIEHS Grant ES-00044 (M.B.G.), and NIH Grant NS22688 (L.M.S.).2 To whom correspondence should be addressed at Neurotoxicology Division [MD-74B] USEPA, R.T.P., NC 27711. E-mail: crofton.kevin® EPAMAIL.EPA.GOV. reiform and circling movements (Delay, 1952; Thullier and Burger, 1954;Selye, 1957) through degeneration of the vestibular system (Slagel and Hartman, 1965;Llorens et al., 1993;Llorens and Dememes, 1994). IDPN has also been associated with auditory and olfactory damage, and proximal axonopathy (Chou and Hartman, 1964;Griffin et al., 1978;Crofton and Knight, 1991;Genter et al, 1992Genter et al, , 1994aCrofton et al., 1994). Currently, the role of metabolism in IDPNinduced neurotoxicity is unclear.Theories on the activation of LDPN have involved three possible metabolic pathways: (1) cytochrome P450 metabolism, (2) monoamine oxidase (MAO) metabolism, and (3) flavin-containing monooxygenase (FMO) metabolism (e.g., Jacobson et al., 1987). It has also been suggested that IDPN is the toxic compound and needs no hepatic bioactivation (Llorens and Crofton, 1991). Tanii et al. (1984) first demonstrated that the neurotoxicity of some related neurotoxic nitriles (e.g., 2-pentenenitrile) was increased by inactivation of hepatic P450s with carbon tetrachloride (CC1 4 ) pretreatment. After observing enhanced v...

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Learning and memory deficits in rats following exposure to 3,3′-iminodipropionitrile

Cited by 29 publications

References 23 publications

Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice

Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice

Electrophysiological Deficiency in Peripheral Nerve Induced by Treatment for 12 Weeks with 2‐Butenenitrile, 3‐Butenenitrile, cis‐2‐Pentenenitrile and 3, 3′‐Iminodipropionitrile in Rats

Effect of Methimazole, an FMO Substrate and Competitive Inhibitor, on the Neurotoxicity of 3,3′-Iminodipropionitrile in Male Rats

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