Muscle sarcomas and alopecia in A/J mice chronically treated with nicotine

AimsTo evaluate the pathobiologic effects of long-term treatment with nicotine of A/J mice susceptible to tobacco-induced lung carcinogenesis.Main methodsExperimental group of mice received subcutaneous injections of the LD50 dose of (−)nicotine hydrogen tartrate of 3 mg/kg/day, 5 days per week for 24 months, and control group received the vehicle phosphate-buffered saline.Key findingsNicotine treated mice, 78.6%, but none of control of mice, developed neoplasms originating from the uterus or skeletal muscle. Examination of the uterine neoplasms revealed leiomyosarcomas, composed of whorled bundles of smooth-muscle like cells with large and hyperchromatic nuclei. Sections of the thigh neoplasms revealed densely cellular tumors composed of plump spindle cells, with occasional formation of ‘strap’ cells, containing distorted striations. Both neoplasms were positive for desmin staining. A solitary pulmonary adenoma with papillary architecture also occurred in one nicotine treated mouse. Experimental mice also developed transient balding starting as small patches of alopecia that progressed to distinct circumscribed areas of complete hair loss or large areas of diffuse hair loss.SignificanceWe demonstrate for the first time that chronic nicotine treatment can induce the development of muscle sarcomas as well as transient hair loss. These findings may help explain the association of childhood rhabdomyosarcoma with parental smoking and earlier onset of balding in smokers. It remains to be determined whether the pathobiologic effects of nicotine result from its receptor-mediated action and/or its tissue metabolites cotinine and N′-nitrosonornicotine, or toxic effects of reactive oxygen species activated due to possible intracellular accumulation of nicotine.