The role of oxidative stress in indium phosphide-induced lung carcinogenesis in rats

Indium phosphide (IP), widely used in the microelectronics industry, was te sted for potential carcinogenicity. Sixty male and 60 female Fischer 344 ra ts were exposed by aerosol for 6 h/day, 5 days/week, for 21 weeks (0.1 or 0 .3 mg/m(3); stop exposure groups) or 105 weeks (0 or 0.03 mg/m(3) groups) w ith interim groups (10 animals/group/sex) evaluated at 3 months. After 3-mo nth exposure, severe pulmonary inflammation with numerous infiltrating macr ophages and alveolar proteinosis appeared. After 2 years, dose-dependent hi gh incidences of alveolar[bronchiolar adenomas and carcinomas occurred in b oth sexes; four cases of squamous cell carcinomas appeared in males (0.3 mg /m(3)), and a variety of nonneoplastic lung lesions, including simple and a typical hyperplasia, chronic active inflammation, and squamous cyst, occurr ed in both sexes. To investigate whether inflammation-related oxidative str ess functioned in the pathogenesis of IP-related pulmonary lesions, we stai ned lungs of control and high-dose animals immunohistochemically for four m arkers indicative of oxidative stress: inducible nitric oxide synthase (i-N OS), cyclooxygenase-2 (COX-2), glutathione-S-transferase Pi (GST-Pi), and 8 -hydroxydeoxyguanosine (8-OHdG). Paraffin-embedded samples from the 3-month and 2-year control and treated females were used. i-NOS and COX-2 were hig hly, expressed in inflammatory foci after 3 months; at 2 years, all four ma rkers were expressed in nonneoplastic and neoplastic lesions. Most i-NOS st aining, mainly in macrophages, occurred in chronic inflammatory and atypica l hyperplastic lesions. GST-Pi and 8-OHdG expression occurred in cells of c arcinoma epithelium, atypical hyperplasia, and squamous cysts. These findin gs suggest that IP inhalation causes pulmonary inflammation associated with oxidative stress, resulting in progression to atypical hyperplasia and neo plasia.