An overview of immunotoxicology and carcinogenic polycyclic aromatic hydrocarbons

Studies with a number of viruses revealed a time-dependent acquisition of interferon (IFN) inducibility in primary chick embryo cells as they "aged" in vitro for 2-12 days at a confluent cell densi...

Interferon induction by viruses. XIV. Development of interferon inducibility and its inhibition in chick embryo cells "aged" in vitro.

Mice were treated with several different potentially carcinogenic components of tobacco smoke. The chemicals used were: 4-aminobiphenyl and aniline-HCl, which are found in high concentrations in sidestream tobacco smoke; hydrazine sulfate, which is found in high concentrations in mainstream tobacco smoke; and 2-methylquinoline, which is found in intermediate concentrations in both sidestream and mainstream smoke. The chemicals were injected i.p. into mice, and then α/β interferon was induced in the mice by i.v. injection of polyriboinosinic-polyribocytidylic acid. The interferon was induced either 2, 24, or 48 hr after treatment with the tobacco smoke components. Mice treated with 4-aminobiphenyl showed some depression of interferon production 2 hr after treatment, maximum inhibition of interferon induction 24 hr after treatment, and a return to control levels of interferon 48 hr after treatment. Mice treated with hydrazine sulfate showed maximum inhibition of interferon induction 24 hr after treatment but no effects at any other treatment time. These components were the most carcinogenic chemicals of those utilized in this study. Treatment of mice with aniline-HCl, a chemical whose carcinogenic potential is still debated, resulted in marginal depression of interferon induction 24 hr after treatment. 2-Methylquinoline, the chemical with the lowest carcinogenic potential in this study, had no effect on interferon induction after administration to mice. In vivo interferon induction was, therefore, inhibited by treatment of mice with chemical carcinogens found in tobacco smoke. The efficacy of the chemical in inhibiting interferon induction was not influenced by the mainstream or sidestream smoke predominance of the chemical.

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Effect of carcinogenic components of cigarette smoke on in vivo production of murine interferon.

Effect of environmental carcinogens and other chemicals on murine alpha/beta interferon production

A system for the simultaneous exposure of monolayer cell cultures to mainstream (MS) and sidestream (SS) smoke from the same cigarette was utilized to study the effects of smoke generation and manipulation variables on the cytotoxicity of smoke to monolayer cultures of mouse fibroblast-like L-929 cells. The cytotoxicity of MS smoke was decreased with increasing smoke age (up to 8.7 s), smoke dilution, and the quantity of activated charcoal in filters. Acetate filters had little effect on cell mortality, and the age-of-smoke effect was not evident for MS smoke generated with a low puff volume and rapid dilution. The cytotoxicity of SS smoke also decreased rapidly with increasing smoke age and dilution. The results indicate that the gas phase of smoke may be of major importance in generating the observed toxic effects. These results may be of potential future significance in defining the requirements for a less toxic cigarette, in considering the hazards of SS smoke, and in evaluating in vivo inhalation studies.

The effect of smoke generation and manipulation variables on the cytotoxicity of mainstream and sidestream cigarette smoke to monolayer cultures of L-929 cells.

Spleens were removed from Swiss Webster mice, and cultures of spleen cells were prepared. Gamma (ty pe II immune) interferon (IFN) production was induced in these cells by addition of the purified protein form of phytohemagglutinin (PHA-P) to the cultures. When 7,12-dimethylbenz[a]anthracene (DMBA) was added to the cultures either before or after addition of PHA-P, the production of gamma IFN was inhibited. The degree of inhibition was greater when the cells were treated with DMBA before addition of PHA-P. In experiments to determine the effects of DMBA on the antivirus activity of previously prepared gamma IFN preparations, DMBA was either added to target cells before the addition of exogenous gamma IFN or mixed together with exogenous gamma IFN. In both cases. the antivirus activity of this exogenous gamma IFN was not affected. These data suggest that DMBA treatment can inhibit the production but not the antivirus activity of murine gamma IFN.

Effect of 7,12-Dimethylbenz[a]anthracene on Production and Action of Gamma Interferon

L-929 cells were treated with benzo-(a)-pyrene (BP), washed, and then interferon(IFN)-alpha/beta was induced with polyriboinosinic-polyribocytidylic acid (poly-I-C). IFN-alpha/beta production by these cells was measured at 6-hour intervals. Up to 24 h after commencement of IFN induction, IFN production was severely inhibited in BP-treated cells as compared to controls. After 24 h, IFN-alpha/beta production in BP-treated cells began to rise and reached levels seen in untreated cells by 48 h. These data indicated that IFN induction was not completely inhibited by BP treatment, but, rather, the peak of IFN production was delayed. Mouse embryo cultures from SENCAR mice showed the same pattern of delayed IFN production when treated with BP. Direct exposure of the cells to BP for at least 15 min prior to removal of the carcinogen was required for IFN induction to be inhibited; however, at least 24 h of further incubation in fresh medium before addition of poly-I-C was required for inhibition of IFN induction by BP.

Kinetics of Inhibition of in vitro Interferon-Alpha/Beta Production after Benzo-(a)-Pyrene Exposure

Mouse L-929 cells were treated with benzo[a]pyrene [(BP) CAS: 50-32-8] for 24 hours. Several cultures of cells were immediately treated with polyriboinosinic-polyribocytidylic acid (poly I:C) to induce interferon-alpha/beta (IFN). Other sets of cultures were washed and allowed to incubate with fresh culture medium for 3-18 hours before addition of poly I:C to induce IFN. The IFN induction was severely inhibited in cells treated with BP and immediately challenged with poly I:C as compared to non-BP-treated cells. Up to a 6-hour delay in addition of poly I:C still resulted in severe inhibition of IFN induction; however, a delay of 9 hours or longer allowed the cells to recover their IFN production capacity. These data indicate that the inhibition of IFN induction by BP was reversible. The number of cells laid down in the cultures was approximately 6 X 10(5). In another experiment, the number of cells laid down in culture was serially decreased in several different cultures. These normal cells were then treated with poly I:C to induce IFN. A 50% decrease in the number of cells was required to reduce IFN production by 50%. In BP-treated L-929 cells, viabilities ranged from 88 to 90%, but IFN induction was inhibited by greater than 50%. These results suggest that toxicity of carcinogens to cells does not play a major role in inhibition of IFN induction by carcinogens.

Reversibility of Inhibition of Interferon-alpha/beta Induction by Benzo[a]pyrene

Embryonic fibroblasts were prepared from four different strains of mice: DBA/2, noninducible at the Ah locus for aryl hydrocarbon hydroxylase for carcinogen activation and, therefore, relatively resistant to tumor induction; C57BL/6, normal at the Ah locus; SENCAR, mice innately highly sensitive to tumor induction; and ICR, normal controls for SENCAR mice. The fibroblasts were exposed to the carcinogen benzo-(a)-pyrene at varying dosages. Alpha/beta IFN was next induced with poly(I)(C). Interferon production by cells from C57BL/6 mice was severely inhibited. Interferon production by DBA/2 cells was equally susceptible to inhibition by BP as IFN production by C57BL/6 cells, perhaps because of alternative pathways of activation of BP. Interferon production by SEN-CAR mouse cells was, on the other hand, much more susceptible to inhibition by BP than was IFN production by ICR mouse cells. These results suggest parallels between genetically controlled sensitivity to tumor induction by BP and genetically contro...

Karen A. Golemboski

Papers

Effect of 7,12-Dimethylbenz[a]anthracene on Production and Action of Gamma Interferon

Kinetics of Inhibition of in vitro Interferon-Alpha/Beta Production after Benzo-(a)-Pyrene Exposure

Reversibility of Inhibition of Interferon-alpha/beta Induction by Benzo[a]pyrene

Genetics of susceptibility of mice to inhibition of interferon induction by benzo-(a)-pyrene.