Elsevier

Toxicology Letters

Volume 92, Issue 1, 16 June 1997, Pages 31-37
Toxicology Letters

Acute hematopoietic toxicity of aniline in rats

https://doi.org/10.1016/S0378-4274(97)00032-5Get rights and content

Abstract

In the present study, acute hematopoietic toxicity of aniline as a function of time was investigated in rats. The animals were given a single oral dose of aniline hydrochloride (2 mmol/kg) and euthanized at zero (control), 0.25, 0.5, 1, 3, 6, 12, 24 and 48 h following the treatment. The blood methemoglobin level increased dramatically and attained a peak level of 37% (31 fold greater than the controls) at 0.5 h. Thereafter, the increases were less pronounced and the level declined with time. Spleen weight to body weight ratio remained unchanged up to 24 h, but increased ∼25% at 48 h. Lipid peroxidation (MDA content) in the spleen increased by 39% at 24 h and remained steady even at 48 h. MDA-protein adducts, as quantitated by a competitive ELISA, showed 94, 126 and 265% increases in the spleen homogenates at 12, 24 and 48 h, respectively, following the treatment. However, no changes were observed in the splenic protein oxidation. Morphological examination showed congestion of splenic blood vessels and marked expansion of red pulp at 24 and 48 h. These studies suggest that aniline related changes in the blood are reflected very early as evident from increases in the methemoglobin content, whereas changes in the spleen appear later and are characterized by splenic weight changes, increased lipid peroxidation, MDA-protein adduct formation and morphological changes after a single high dose exposure. The increased lipid peroxidation in the spleen also suggests that free radical-mediated reactions could be the potential mechanism of splenic toxicity of aniline and lipid peroxidation precedes protein oxidation.

Introduction

Aniline is one of the most widely used industrial chemicals, especially in dye and drug industry. Early toxicity of aniline is generally associated with methemoglobin formation and damage to erythrocytes (Jenkins et al., 1972; Kim et al., 1986; Bus and Popp, 1987). In experimental animals, however, aniline exposure results in selective toxicity to the spleen which is characterized by hyperplasia, hyperpigmentation, siderosis, fibrosis, and a variety of sarcomas on chronic exposure (Bus and Popp, 1987; Kahn et al., 1995a). The initial cellular and molecular events leading to the selective splenic toxicity of aniline are not well understood.

Our earlier findings suggest that initial interaction between erythrocytes and aniline could be an important event leading to splenic toxicity (Kahn et al., 1995a; Kahn et al., 1995b). In our multiple dose and subchronic studies, we have shown that aniline exposure in rats results in iron deposition in the spleen (Kahn et al., 1995a, Kahn et al., 1993) which may catalyze the generation of reactive oxygen species and other free radicals to initiate such events as lipid peroxidation, protein and DNA oxidation (Kehrer, 1993). Indeed, we have observed increased lipid and protein oxidation in spleen following exposure to aniline using multiple dose regimen (Kahn et al., 1997). However, information on time-dependent response of acute single dose exposure on these events is not known and is investigated in this study.

Section snippets

Animals and treatment

Male Sprague-Dawley rats (∼200 g), obtained from Harlan Sprague-Dawley (Indianapolis, IN) were housed in wire-bottom cages over absorbent paper with free access to tap water and Purina lab chow. The rats were acclimatized in a controlled environment animal room (temperature, 22°C; relative humidity, 50%; photoperiod, 12-h light/dark cycle) for 7 days prior to the treatment.

Animals were given 2 mmol/kg of aniline hydrochloride (AH) orally in 0.5 ml of tap water except the control group (zero

Time-course acute effects on methemoglobin levels

Changes in the blood methemoglobin contents of rats treated with aniline are summarized in Table 1. As early as 0.25 h of aniline exposure, methemoglobin level increased dramatically (26.5 fold) and attained the peak at 0.5 h (37%, 31 fold). Thereafter, the increases were not as dramatic but still higher by ∼11 and 7 fold at 1 and 3 h, respectively. By 6 h, the increase in the methemoglobin level was only over 2 fold and maintained similar levels even at 48 h.

Response of spleen to acute aniline exposure

No change in the body weights was

Discussion

The focus of this study was to understand the onset of splenotoxic effects and to determine the kinetics of methemoglobin formation as a result of acute aniline intoxication in rats. The time sequence of the hematopoietic changes, especially in the spleen, is important in identifying the earliest events leading to tissue injury.

Oral LD50 for AH in rats has been reported to be 440 mg/kg (Jacobson, 1972). Higher incidences of splenic tumors were encountered when rats were treated for 2 years with

Acknowledgements

This study was supported by Grant ES 06476 (awarded to MFK) from National Institute of Environmental Health Sciences, NIH.

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