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. 2019 May 23;17(2):1559325819852233.
doi: 10.1177/1559325819852233. eCollection 2019 Apr-Jun.

Time-Course Evaluation of Iminodipropionitrile-Induced Liver and Kidney Toxicities in Rats: A Biochemical, Molecular and Histopathological Study

Manar A Alwelaie  1 , Mohsen G Al-Mutary  2 , Nikhat J Siddiqi  1 , Maha M Arafah  3 , Abdullah S Alhomida  1 , Haseeb A Khan  1
Affiliations

Time-Course Evaluation of Iminodipropionitrile-Induced Liver and Kidney Toxicities in Rats: A Biochemical, Molecular and Histopathological Study

Manar A Alwelaie et al. Dose Response. .

Abstract

Iminodipropionitrile (IDPN) is known to produce axonopathy and vestibular hair cell degeneration. Recent histopathological studies have shown IDPN-induced liver and kidney toxicities in rodents; however, the associated mechanisms are not clearly understood. We investigated the role of proinflammatory cytokines in IDPN-induced liver and kidney toxicities in rats. Rats were treated with saline (control) and IDPN (100 mg/kg, intraperitoneally) daily for 1, 5, and 10 days, respectively. Animals were killed 24 hours after the last dose and liver and kidneys were collected for histopathology and interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α messenger RNA expression analysis. Serum aspartate aminotransferase and alanine aminotransferase activities were significantly increased after 10 doses of IDPN. The level of serum creatinine was initially increased after the first dose of IDPN but subsided on days 5 and 10. Blood urea nitrogen levels were significantly increased on days 5 and 10 following IDPN exposure. Histopathology showed dose-dependent hepatotoxicity in IDPN-treated rats. Iminodipropionitrile-induced expression of proinflammatory cytokines peaked after day 1 in liver and after day 5 in kidneys. In conclusion, repeated exposure of IDPN for 10 days produced significant structural and functional damages in rat liver whereas kidneys showed gradual recovery with time. These findings point toward the role of inflammatory mediators in IDPN-induced toxicity in rats.

Keywords: iminodipropionitrile; kidney; liver; proinflammatory cytokines; toxicity.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Effect of different daily doses of IDPN on serum markers of liver function: (A) serum ALT and (B) serum AST. *P < .05 and **P < .01 versus control group using Dunnett test. IDPN indicates iminodipropionitrile.
Figure 2.
Figure 2.
Effect of different daily doses of IDPN on serum markers of kidney function: (A) blood urea nitrogen and (B) serum creatinine. *P < .05 and **P < .01 versus control group using Dunnett test. IDPN indicates iminodipropionitrile.
Figure 3.
Figure 3.
Effect of different treatments of IDPN on mRNA expression of (A) IL-1β, (B) IL-6, and (C) TNF-α in rat liver. *P < .05 and **P < .01 versus control group using Dunnett test. IDPN indicates iminodipropionitrile; mRNA, messenger RNA.
Figure 4.
Figure 4.
Effect of different treatments of IDPN on mRNA expression of (A) IL-1β, (B) IL-6, and (C) TNF-α in rat kidney. *P < .05 and **P < .01 versus control group using Dunnett test. IDPN indicates iminodipropionitrile; mRNA, messenger RNA.
Figure 5.
Figure 5.
Effect of different daily doses of IDPN on histopathological changes in rat liver. A, Control rat with normal liver cells, portal tract and veins. B, Iminodipropionitrile (1 dose), few mononuclear infiltrations in the portal tract. C, Iminodipropionitrile (5 doses), portal tract with infiltration of mononuclear inflammatory cells and a few hepatocytes with microsteatosis. D, Iminodipropionitrile (10 doses), portal tract with mononuclear inflammatory cell infiltrate, microsteatosis, and degeneration of hepatocytes (H&E staining, magnification 400×). IDPN indicates iminodipropionitrile.
Figure 6.
Figure 6.
Effect of different daily doses of IDPN on histopathological changes in rat kidney. A, Control rat kidney with normal glomerulus and renal tubules. B, Iminodipropionitrile (1 dose), glomerulus with increased mesangial cells and a few neutrophil cells. C, Iminodipropionitrile (5 doses), glomeruli with increased mesangial cells. D, Iminodipropionitrile (10 doses), renal glomeruli and tubules with no apparent changes (H&E staining, magnification 400×). IDPN indicates iminodipropionitrile.
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