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Transformation of C3H/10T Mouse Embryo Cells to Focus Formation and Anchorage Independence by Insoluble Lead Chromate but not Soluble Calcium Chromate: Relationship to Mutagenesis and Internalization of Lead Chromate Particles¹

Department of Microbiology and USC Comprehensive Cancer Center, Norris Cancer Hospital and Research Institute, University of Southern California School of Medicine, Los Angeies, California 90033.

The genotoxicity of soluble and insoluble hexavalent chromium compounds was studied in mammalian cell assays which detect base substitution, deletion, addition, and frameshift mutations [6-thioguanine resistance in Chinese hamster ovary cells], primarily base substitution mutations [ouabain resistance in Chinese hamster ovary and C3H/10T Cl 8 mouse embryo fibroblasts (10T)] and morphological transformation [focus formation] in 10T cells. Soluble hexavalent CaCrO₄, administered in either acute (5-h) or subacute (24-h) dosing regimens, induced dose-dependent cytotoxicity and mutation to 6-thioguanine resistance in Chinese hamster ovary cells but no mutation to ouabain resistance or focus formation in transformation assays, although the acute treatment induced a high frequency of conversion of 10T cells to adipocytes. Cell lines established from cloned adipocytic cells were not morphologically transformed and did not grow in soft agarose. PbCrO₄ did not induce mutation to either 6-thioguanine or ouabain resistance but did induce a reproducible dose-dependent, low frequency of focus formation in 10T cells. Cell lines established from PbCrO₄-induced foci stably formed foci when coseeded with 10T cells, had 3–5-fold increased saturation densities relative to nontransformed 10T cells, and formed colonies in soft agarose, indicating their likelihood to be neoplastic. Long term exposure of 10T cells to either CaCrO₄ or PbCl₂, even at 85% cytotoxic concentrations, or pretreatment of cells with either CaCrO₄ or PbCl₂ followed by treatment with the alternate compound, did not induce morphological transformation. Treatment of cells with insoluble hexavalent PbCrO₄ resulted in progressive and extensive vacuolization of cells in contact with the particles. Progressive cytoplasmic engulfment of PbCrO₄ particles was observed using scanning electron microscopy, although PbCrO₄ particles were not observed inside vacuoles.

These results indicated that the soluble clastogens K₂Cr₂O₇ and CaCrO₄ were probably mutagenic by a non-base substitution mechanism but could not transform 10T cells. In contrast, PbCrO₄ was not detectably mutagenic but induced transformation, which could not be explained solely by acute or chronic exposure to dissolution products of either lead or chromate alone. Since PbCrO₄ particles were found to be intracytoplasmic in extensively vacuolated cells, we suggest that the unique physicochemical properties of PbCrO₄ particles, leading to their internalization and the resultant associated cellular stress response, may be related to the transformation induced by this compound.

¹ This work was supported by Grant ES03341 from the National Institute of Environmental Health Sciences, NIH, and by a grant from the R. J. Reynolds Company to Joseph R. Landolph.

² Supported by National Cancer Institute (NIH) Training Grant T32 CA 09320 in Chemical and Viral Carcinogenesis and a National Institute of Environmental Health Sciences Individual Postdoctoral Fellowship Award. Present address: Department of Pharmacology, George Washington University Medical School, 2300 Eye St. N.W., Washington, DC 20337.

³ To whom requests for reprints should be addressed, at USC Comprehensive Cancer Center, K. Norris Jr. Cancer Hospital, Department of Microbiology, Box 33800, 2025 Zonal Ave., Los Angeles, CA 90033-0800.

Received 1/15/88. Revised 5/11/88. Accepted 6/21/88.

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