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Growth stimulation of primary rat hepatocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin

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Abstract

The modulation of liver growth control by the tumor promoter, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), was investigated in primary hepatocytes of adult rats. Under defined conditions in serum-free cultures, the interaction of TCDD with growth-related hormones was studied. TCDD-treatment of the cultured hepatocytes for two days caused a transient stimulation of both DNA synthesis and mitotic activity. This effect was maximal at the very low nontoxic concentration of 10−12 M TCDD, i.e., two orders of magnitude below the optinzal concentrations for induction of drug metabolizing enzymes. Growth stimuladon by TCDD was dependent on the presence of growth-related hormones; in primary rat hepatocytes, TCDD acted synergistically with insulin and epidermal growth factor (EGF) and antagonized the growth inhibition by dexamethasone. Under culture conditions allowing high rates of DNA synthesis, e.g., at low concentrations of dexamethasone, in the presence of EGF plus alphal-adrenergic agonists or rat serum, no significant effect of TCDD on cellular growth was observed. Furthermore, TCDD failed to stimulate DNA synthesis in a rat hepatoma cell line, H4IIE, which is less sensitive to growth controlling factors than normal hepatocytes. Therefore, the results suggest that the growth modulation of primary rat hepatocytes by TCDD is the most sensitive parameter of the agent thus far observed. This effect may involve both a release from the growth inhibition caused, for instance, by glucocorticoids, as well as a direct growth-stimulating effect, synergistic to the one induced by insulin.

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Abbreviations

Ah:

aryl hydrocarbon

EGF:

epidermal growth factor

EROD:

7-ethoxyresorufin-0-deethylase

3HdT:

[3H]thymidine

TCB:

3,4,3′,4′-tetrachlorobiphenyl

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

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  1. Department of Toxicology, University of Hamburg Medical School, Grindelallee 117, D-2000, Hamburg 13, Germany

    Detlef Wölfle, Elke Becker & Christoph Schmutte

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Wölfle, D., Becker, E. & Schmutte, C. Growth stimulation of primary rat hepatocytes by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cell Biol Toxicol 9, 15–31 (1993). https://doi.org/10.1007/BF00755137

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