Immunotoxicity of cephalosporins in mice.

This study was performed in female B6C3F1 mice to confirm previously observed effects of selected cephalosporin antibiotics on nonspecific immunity, and to determine possible effects on specific acquired immunity and host resistance. Mice were treated intravenously with DQ-2556, ceftizoxime or ceftezole at 800 mg/kg/day for 3, 5, or 7 consecutive days. All three compounds increased total serum IgM levels from day 3, but had no effects on total serum IgG levels and the thymus weight. All three cephalosporin antibiotics caused a slight increase in spleen weight and splenic germinal centers were enlarged after 5- or 7-day treatments. Antibody responses to type III pneumococcal polysaccharide (S3), a T-cell-independent immunogen, and sheep red blood cells (SRBC), a T-cell-dependent immunogen, were slightly decreased after 5-day dosings with each compound, and reached significance in DQ-2556 (response to S3) and ceftizoxime (response to S3 and SRBC). None of the tested cephalosporin antibiotics altered delayed-type hypersensitivity to oxazolone or host resistance to Plasmodium yoelii, indicating that the antibiotic-treated mice retained the capacity to mount a multicomponent and sustained protective immune response. These data suggest that although cephalosporins may cause polyclonal expansion of B cells with associated increases in total serum IgM, they do not affect the tested measures of cell-mediated immunity or host resistance. The decreased IgM antibody responses to S3 and SRBC are associated with but not known to be causally related to the concurrent IgM hypergammaglobulinemia.

Effect of nitrous oxide exposure on maternal and embryonic S-adenosylmethionine levels and ornithine decarboxylase activity.

Nitrous oxide is suspected to be a developmental toxicant in humans. The anesthetic does produce increases in the resorption and malformation frequencies in rodents. The mechanism for the drug's developmental toxicant effects is unknown. Embryonic DNA synthesis is decreased; however, this decrease does not appear to be due to depressed levels of adenine or guanine. In this investigation, we examined the effect of N2O on maternal and embryonic S-adenosylmethionine (AdoMet) levels and ornithine decarboxylase (ODC) activity, and the effect of exogenous methionine (Met) on these parameters was also examined. AdoMet and ODC are involved in polyamine synthesis, and polyamines are involved in regulation of macromolecular synthesis. Pregnant rats were treated with N2O for 24 hours beginning on the morning of day 10 of gestation. There was no effect of N2O on maternal hepatic AdoMet or S-adenosylhomocysteine (AdoHcy) levels; there was also no effect on embryonic AdoMet. Embryonic AdoHcy could not be detected in many of the samples; however, N2O treatment did significantly increase the number of embryonic samples in which AdoHcy was detectable. ODC activity was not affected by either treatment in dams but was increased by N2O in embryos. It is possible that the embryotoxic effect of this anesthetic is mediated by alterations in the AdoMet to AdoHcy ratio or to changes in ODC activity and polyamine synthesis.

Models for assessing the effect of toxicants on immunocompetence in mice. II. Effect of cyclophosphamide on the antibody responses to type III pneumococcal polysaccharide and tetanus toxoid in BALB/c female mice.

A mixture of antigens was used to detect alterations in immunocompetence. Type III pneumococcal polysaccharide (S3) and tetanus toxoid (TT) stimulate different cellular components, and can therefore be used to assess different compartments of the immune mechanism. Cyclophosphamide (CP), a known immunosuppressant, had a potent effect upon the antibody responses to both S3 and tetanus toxoid. All doses of CP administered within 2 days of priming with S3 resulted in a dose-related immunosuppressive action which persisted even after reinjection of S3. 300 mg/kg of CP given up to 14 days prior to or following primary immunization resulted in a marked suppression of antibodies to S3. Doses of S3 which were partially tolerogenic were made even more so by injections of CP. The effect persisted over a 96 day experimental period. CP also suppressed the formation a memory cells necessary for induction of a secondary-type IgG response to TT. The time of injection for maximum suppression was days 10 to 14 after priming. Therefore, the suppression must involve cellular mechanisms different from those responsible for S3 antibody suppression. In addition, there was a difference in the degree and persistence of the suppressive effect, since the suppressed animals were able to mount an immune response to subsequent injections of TT. Double injections of a high dose (300 mg/kg) of CP 4 weeks after priming completely suppressed the acquired immunity to both S3 and TT. Low and moderate doses of CP appeared to induce a mild augmentation of S3 antibody response when given 4 weeks after priming. However, an immunosuppressive effect occurred if the primed animals were reinjected with S3 or challenged with TT within a period of 2 days prior to or after receiving the CP treatment. Doses of CP, injected prior to challenge and resulting in suppressed tetanus antitoxin production, elevated the titers of specific IgE antibody. This class of antibody is associated with adverse hypersensitivity reactions. These data provided background for the development of models to assess immunocompetence in mice, based on a study of immune profiles following exposure to selected T-dependent and T-independent antigens. Such models may be used to detect potentially hazardous chemicals found in the environment of incorporated into foods, drugs, or cosmetics.