Potential role of alpha-2 mu-globulin, protein droplet accumulation, and cell replication in the renal carcinogenicity of rats exposed to trichloroethylene, perchloroethylene, and pentachloroethane.

Trichloroethylene (TCE), perchloroethylene (PER), and pentachloroethane (PENT) are used extensively as industrial solvents. These agents cause an increased incidence of renal tumors in male, but not female, rats. Male and female F-344 rats were gavaged for 10 days with TCE (1000 mg/kg), PER (1000 mg/kg), and PENT (150 mg/kg) to determine if chlorinated hydrocarbon-induced changes in levels of renal alpha-2 mu-globulin (alpha 2 mu), protein droplet accumulation (PDA), and cell replication were male rat specific. The animal strain, dose, and route of administration were the same as previous chronic bioassays in order to better understand the relationship between alpha 2 mu, PDA, and cell replication to the sex-specific renal carcinogenicity. In male rats, increases in protein droplet and crystalloid accumulation in the cytoplasm of the P2 segment of the proximal tubule were evident after PER and more notably PENT administration. Cell replication rates in male rats increased specifically in the histologically damaged P2 segments after PER or PENT exposure. Protein droplets and cell replication did not differ from controls in TCE-treated male rats or in female rats treated with TCE, PER, or PENT. Immunohistochemical staining for alpha 2 mu revealed a marked correlation between the presence of alpha 2 mu and the protein droplets. Renal alpha 2 mu concentrations in male rats increased after PER or PENT but not TCE administration. The protein droplet nephropathy induced in male rats after PER and PENT treatment appears identical to that observed with other male-rat-specific renal carcinogens such as unleaded gasoline. The differences observed in male and female rats after chlorinated hydrocarbon exposure suggest that increases in cell replication may be directly linked to the male-rat-specific protein alpha 2 mu. Since compensatory cell division is postulated to affect all stages of the carcinogenic process, the increased incidence of renal tumors in male rats after PER or PENT treatment may be related to nephrotoxicity and resulting enhanced cell replication. Mechanisms involved in TCE-induced renal carcinogenicity appear to be different from PER- and PENT-induced renal carcinogenicity.