Effects of Hypothyroidism on Development of Nitrosomethylurea-Induced Tumors of the Mammary Gland, Thyroid Gland, and Other Tissues

Abstract

Female rats were injected with the mammary gland carcinogen N-nitrosomethylurea (NMU) and were made hypothyroid by treatment with either propylthiouracil (PTU) or 131I. NMU (25–100 mg/kg) itself caused a dose-related increase in serum thyroxine levels. PTU (1.0–3.0 mg/100 ml of drinking water) caused a decrease in serum thyroxine and triiodothyronine levels in NMU-treated rats. At 28–31 weeks after injection of NMU alone, 9/43 rats (21%) had malignant mammary tumors. This incidence was increased to 11/30 (37% P > 0.1) and 13/30 (43% P < 0.05) in rats treated with PTU doses of 0.3 and 1.0 mg/100 ml, respectively. In contrast, the 3 mg/100 ml dose of PTU reduced the tumor incidence to 2/30 rats (7%, 0.1 > P > 0.05) and caused a 33% decrease in final body weight. Treatment with 10 μCi of 131I gave a small decrease in serum thyroxine levels in NMU-treated rats and increased the incidence of malignant mammary tumors to 11/26 rats (42%, 0.1 > P > 0.05). In addition, PTU (0.3 mg/100 ml) plus NMU induced a 23% incidence (7/30 rats) of malignant thyroid tumors, and PTU doses of 1.0 or 3.0 mg/100 ml plus NMU led to a 100% incidence of these tumors. With the 0.3 mg/100 ml dose of PTU, there was an increase in the incidence of lung adenomas, whereas with the 3.0/100 ml dose there was a decrease. Thus, this study demonstrates that in NMU-treated rats: (1) slight hypothyroidism favors development of mammary and lung tumors, (2) severe hypothyroidism produces the opposite effect together with weight loss, and (3) the combination of PTU treatment and the carcinogen is followed by malignant thyroid tumors.