Early life inorganic lead exposure induces testicular teratoma and renal and urinary bladder preneoplasia in adult metallothionein-knockout mice but not in wild type mice.
Inorganic lead compounds are carcinogenic in animals and have carcinogenic potential in humans. In mice, lead (Pb) is a transplacental carcinogen in the kidney. Metallothionein (MT) is a metal-binding protein that can reduce the toxicity of various metals, including Pb, either by direct sequestration or as an antioxidant for metals that generate reactive oxygen species. Although MT appears to reduce Pb carcinogenicity in adult mice it is unknown how MT deficiency may affect Pb carcinogenicity from early life exposure. Thus, groups (n=10) of pregnant MT-I/II double knockout (MT-null) or 129/SVJ MT wild type (WT) mice were exposed to Pb acetate in the drinking water (0, 2000, 4000ppm Pb) from gestation day 8 through birth and during lactation. Maternal drinking water Pb exposure continued to wean at 4 weeks of age and the male offspring were then directly exposed to Pb until 8 weeks of age and observed until 2 years old. High dose (4000ppm) but not low dose (2000ppm) Pb reduced survival in the latter part of the study in both MT-null and WT mice. In MT-null mice, but not WT, early life Pb exposure caused a dose-related increase in testicular teratomas, to a maximum incidence of 28% compared to control (4%). Pb-induced renal cystic hyperplasia, considered preneoplastic, was a prominent occurrence in MT-null mice but nearly absent in WT mice. Pb dose-related increases in renal cystic hyperplasia occurred in adult MT-null with early life exposure with maximal incidence of 52%. Pb-treated MT-null mice also showed dose-related increases in urinary bladder hyperplasia with occasional papilloma that were absent in WT mice. Thus, MT deficiency made mice more sensitive to early life Pb exposure with regard to testes tumors, and renal and urinary bladder preneoplastic lesions.
Tokar
Erik J
EJ
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Diwan
Bhalchandra A
BA
Waalkes
Michael P
MP
D000818:Animals; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced; D052177:Kidney Diseases, Cystic / Q000139:chemically induced; D007854:Lead / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000139:chemically induced; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013724:Teratoma / Q000139:chemically induced; D013736:Testicular Neoplasms / Q000139:chemically induced; D001745:Urinary Bladder Diseases / Q000139:chemically induced
D002274:Carcinogens, Environmental; D007854:Lead; D008668:Metallothionein