Morphological alterations in the epithelium of the oral mucosa of rats (Rattus norvegicus) submitted to long-term systemic nicotine treatment

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Abstract

Smoking is considered to be the most albeit preventable cause of diseases and premature deaths in the history of mankind. The local action of tobacco on the oral mucosa can cause precancerous and cancerous lesions. However, there is not enough evidence to establish all the systemic effects caused by nicotine on the organism. Thus, the aim of the present study was to characterize the cellular changes of the cheek mucosa of rats submitted to long-term systemic nicotine treatment. Twenty male rats were divided into two experimental groups: a nicotine group and a control group, each consisting of 10 animals. The nicotine group was injected daily with 0.250 mg of nicotine per 100 g of body weight. All animals received a solid diet and water ad libitum. After 90 days of treatment, all animals were weighed and sacrificed. Samples of cheek mucosa were collected for light and transmission electron microscopy. The results revealed oral epithelium containing atypical cells that were characterized by atrophy, cell membrane disorganization and tissue damage. It was concluded that systemic administration of nicotine damaged the cellular integrity of the oral mucosa, impairing tissue function and predisposing the tissue to the action of different pathogenic agents and also to that of other carcinogenic substances present in tobacco.

Introduction

Tobacco is currently the most widely used drug in the world. The habit of smoking was introduced in Europe by the Portuguese and Spaniards in the 16th century, and has since then been growing, especially among young individuals.1, 2 In the United States, 2200 youngsters per day experiment cigarettes for the first time, and about 830 become regular users.3 More than 4000 substances can be isolated from a cigarette, with nicotine being the substance responsible for addiction, along with other harmful effects.4, 5, 6, 7

Experimentally, the short-term systemic toxicity of tobacco and its components has been reported. Rats submitted to oral chronic nicotine administration were affected by inflammatory process, vascular obliteration and vasospasm, as well as changes in urine pH.8, 9, 10 In addition to this, nicotine administration for 10 days aggravates ethanol gastric ulceration in rats.11 Morphologic alterations in the microvasculature of the oral mucosa were observed in rats after treatment with systemic nicotine for 2 weeks, which may have implications for the role of chronic tobacco use in the etiology of oral mucosal disease.12 Also, the effects of systemic nicotine, after 4 weeks, was analyzed in Hamsters, where diminishing prostaglandin receptors could be noted. These are important elements to keep the structure of the oral mucosa.13 In rodents, it was possible to see the alteration of keratinocytes, which are responsible for regulating the physiology of the cell cycle, after systemic treatment with products of tobacco for 3 weeks.14 Moreover, Pinto et al. verified that local nicotine treatment is harmful to the alveolar bone, specially, in stromal disorganization and osteogenesis.15 Another study, where rodents were submitted to local tobacco effects for 26 weeks, characterized acanthosis, hyperqueratosis, hyperplasia and increasing granular cells of the oral mucosa, specially, the increase of the keratin granules.16, 17

Clinical and experimental studies also have been specifically observed the local effects of tobacco on the oral mucosa predisposed to the occurrence of precancerous and cancerous lesions.2, 8, 18, 19, 20, 21, 22, 23, 24 In the United States, oral and esophageal cancers account for approximately 3% of all malignant diseases in men and for 2% in women.25 Oral problems related to abrasion, hypersensitivity of mineralized tissues and acute necrotizing ulcerative gingivitis has also been associated with tobacco use.26, 27, 28, 29, 30 Hyperkeratosis and leukoplasia are also common in smokers, affecting the lips, tongue and cheek mucosa, and may progress to precancerous processes.21, 24 These studies support the theory that the chemical exposure to tobacco specially the local action can cause cellular alteration. However, there is not enough evidence to establish all systemic effects caused by nicotine on the organism.31 According to Ringdahl et al. the oral mucosa showed no histological alteration or changes in the epithelial cell proliferation after administering nicotine for 6 weeks.32 Also, Jarvis and Witehead when studying the gastric mucosa of rats submitted to systemic nicotine treatment did not observe important cell alteration.33

Thus, in view of the known importance of the structure of the oral mucosa for protection against aggressive agents, as well as the direct association between function and structure, the aim of the present study was to characterize the cellular changes of the cheek mucosa of rats submitted to long-term systemic nicotine treatment.

Section snippets

Animals and organ preparation

Twenty week-old male Wistar rats (Rattus norvegicus), provide by the Animal Care Center (CEMIB/the State University of Campinas), were divided into two groups: a nicotine group with 10 animals injected subcutaneously on the dorsum with 0.250 mg of nicotine per 100 g of body weight (Nicotine, Sigma, St. Louis, USA) daily, and a control group of 10 animals which received physiological saline under identical conditions.31 The water and ration (Nuvilab CR1, the state of São Paulo, Brazil) were ad

Nutritional analysis

No significant differences in fluid and solid intake or body weight variation were observed between the two groups. All animals gained weight during the experimental period.

Control group (Fig. 1A)

The mean thickness of the stratified squamous epithelium was 9.4 μm, with the epithelium showing epithelial cristae located above the basement membrane (Table 1). In the basal layer, columnar cells with nucleus were noted. Above this the spinous and granular layers were characterized by spherical and polyhedral cells,

Discussion

Malnutrition is characterized by a loss of body weight, in addition to changes in other physical parameters such as hair loss.44 In the present study no significant variations in body weight gain or solid and fluid intake were observed, demonstrating the absence of malnutrition in animals submitted to systemic nicotine treatment. Due to this, any harmful morphological alteration which occurred originated from nicotine action on the oral mucosa. Jarvis and Witehead reported that the oral

Acknowledgments

FAEP-Unicamp, CNPq and FAPESP.

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