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Toxicologic Pathology
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Human Natural Tumor Necrosis Factor {alpha} Induces Multiple Endocrine and Hematologic Disorders in Rats

Chihaya Kakinuma

Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan

Yoshimasa Hamada

Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan

Yoshihiro Futamura

Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan

Chitose Kuwayama

Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan

Akihito Shimoi

Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan

Yasunori Shibutani

Toxicology Laboratory, Mochida Pharmaceutical Co., Ltd., 342 Gensuke, Fujieda, Shizuoka 426-8640, Japan

Slc:Wistar male rats treated with human natural tumor necrosis factor {alpha} (hn TNF-{alpha}, 3 X 105 Japan reference units/kg intravenously) for 3 months showed histologic vacuolation of basophils in the anterior pituitary, hyperplasia of the thyroidal follicular epithelium, and hyperplasia of the testicular interstitial cells. The vacuolated basophils were immunohistochemically shown to be thyrotrophs. In addition, there were decreases in plasma levels of triiodothyronine (T3), thyroxin (T4), and testosterone, and an increase in thyroid-stimulating hormone (TSH). The number of lymphocytes in the marginal zones of lymphoid follicles in spleen and lymph nodes and B-lymphocytes in the peripheral blood decreased. Hyperplasia of hematopoietic cells in the bone marrow and decreases in both leukocytes and erythrocytes in the peripheral blood were prominent. Hyperplasia of bile ductular epithelial cells with periportal mononuclear cell infiltration in the liver and increased cellularity in alveolar walls in the lung were also characteristic. In in vitro studies, hn TNF-{alpha} inhibited both proliferation and peroxidase activity of thyroid follicular epithelial cells. These findings demonstrate that hn TNF-{alpha} may induce histologic vacuolation of thyrotrophs by causing a decrease in plasma levels of T3 and T4; hyperplasia of the thyroid follicular epithelium, which may be attributed to the increased plasma level of TSH; hyperplasia of testicular interstitial cells, by lowering the plasma level of testosterone; hyperplasia of bile ductular epithelial cells; hyperplasia of hematopoietic cells in bone marrow; and the increase in cellularity in pulmonary alveolar walls. In addition, hn TNF-{alpha} may suppress the differentiation of B-lymphocytes.

Key Words: Human natural tumor necrosis factor {alpha} • pathology • flow cytometry • thyrotroph • thyroid-stimulating hormone • thyroid hormones • testosterone • rats

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Toxicologic Pathology, Vol. 27, No. 4, 402-411 (1999)
DOI: 10.1177/019262339902700403
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