title: Modification of dietary copper levels on the early stage of tumor-promotion with propylthiouracil in a rat two-stage thyroid carcinogenesis model.
abstract: To investigate the role of copper (Cu)-related cellular responses on thyroid carcinogenesis, the expression of ceruloplasmin (Cp) and metallothionein (MT)-1/2 were examined in relation to the activities of cell proliferation/apoptosis in the thyroid of rats at an early stage of tumor promotion under different dietary Cu levels. Male F344 rats were initiated with N-bis(2-hydroxypropyl)nitrosamine by single subcutaneous injection at 2800 mg/kg body weight, and 1 week later promoted with 6-propyl-2-thiouracil at 12 ppm in the drinking water for 4 weeks. Animals were fed a diet containing Cu at 0.6, 6 or 60 ppm from the time point of initiator-treatment to create marginally deficient, normal, or non-toxic supplementary levels of Cu. At both 0.6 and 60 pm, the multiplicity of preneoplastic focal follicular cell hyperplasias (FFCHs) was decreased as compared with 6 ppm Cu, while adenomas also decreased at 0. 6 ppm Cu. Both 0.6 and 60 ppm Cu levels revealed decreased Ki-67-immunoreactive proliferating cells in both FFCHs and surrounding follicles accompanied by mRNA downregulation of Cdc2a and Ccnb1, while TUNEL-positive apoptotic cells were unaltered with change of dietary Cu. Both Cp and MT-1/2 were immunolocalized in FFCHs and adenomas, with higher distribution in the latter. At both 0.6 and 60 ppm, the immunoreactivities and/or thyroidal mRNA levels of Cp and MT-1/2 were also decreased. Transcript levels of several antioxidant enzymes were up- or downregulated in the same direction at both Cu levels. Serum levels of thyroid-related hormones were unaltered at both Cu levels, except for non-significant reduction of thyroid-stimulating hormone at 0.6 ppm. These results suggest an involvement of Cp and MT-1/2 on the thyroid tumor promotion that can be suppressed by dietary Cu level through inhibition of cell proliferation associated with altered redox balance.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shima
authors.forename: Jihei
authors.initials: J
authors.lastname: Nishimura
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Dewa
authors.forename: Yukie
authors.initials: Y
authors.lastname: Saegusa
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Masaomi
authors.initials: M
authors.lastname: Kawai
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Harada
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism; D003300:Copper / Q000097:blood / Q000494:pharmacology*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D007501:Iron / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D018384:Oxidative Stress; D011441:Propylthiouracil / Q000494:pharmacology*; D051381:Rats; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000139:chemically induced*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D014284:Triiodothyronine; D011441:Propylthiouracil; D003300:Copper; D013972:Thyrotropin; D008668:Metallothionein; D007501:Iron; D002570:Ceruloplasmin; D013974:Thyroxine