Oral subchronic immunotoxicity study of ethyl tertiary butyl ether in the rat.

The potential for immunotoxicological effects of ethyl tertiary butyl ether (ETBE, CAS RN 637-92-3) was studied in young adult female Crl:CD(SD) rats following subchronic oral exposures. Rats were exposed by gavage once daily for 28 consecutive days to 0, 250, 500, or 1000 mg ETBE/kg body weight (BW)/day; a concurrent positive control group received four intraperitoneal injections of at 50 mg cyclophosphamide monohydrate (CPS)/kg/day on study Days 24-27. Immunotoxicity was evaluated using a splenic antibody-forming cell (AFC) assay to assess T-cell-dependent antibody responses in rats sensitized with sheep red blood cells (SRBC). All rats survived to the scheduled necropsy. There were no effects on clinical observations, body weights, feed or water consumption, or macroscopic pathology findings in the ETBE-treated rats. No ETBE-related effects were observed on absolute or relative (to final body weight) spleen or thymus weights, spleen cellularity, or on the specific (AFC/10(6) spleen cells) or total activity (AFC/spleen) of splenic IgM AFC to the T-cell-dependent antigen SRBC. CPS produced expected effects consistent with its known immunosuppressive properties and validated the appropriateness of the AFC assay. Based on the results of this study, ETBE did not suppress the humoral component of the immune system in female rats. The no-observed-effect level for immunotoxicity was the highest dosage tested at 1000 mg/kg/day.

Safety of oral sulfates in rats and dogs contrasted with phosphate-induced nephropathy in rats.

An oral sulfate salt solution (OSS), under development as a bowel cleansing agent for colonoscopy in humans, is studied in rats and dogs. In rats, amaximumpractical oral OSS dose (5 g/kg/d) is compared with an oral sodium phosphate (OSP) solution, both at about 7 times the clinical dose. OSS induces the intended effects of loose stools and diarrhea. In rats, higher urine sodium and potassium accompany higher clearance rates, considered adaptive to the osmotic load of OSS. OSS for 28 days is well tolerated in rats and dogs. In contrast, OSP causes increased mortality, reduced body weight and food consumption, severe kidney tubular degeneration, and calcium phosphate deposition in rats. These are accompanied by mineralization in the stomach and aorta, along with cardiac and hepatic degeneration and necrosis. The greater safety margin of OSS over OSP at similarmultiples of the clinical dose indicates its suitability for human use.

Thymus-derived glucocorticoids are insufficient for normal thymus homeostasis in the adult mouse.

BACKGROUND: It is unclear if thymus-derived glucocorticoids reach sufficient local concentrations to support normal thymus homeostasis, or if adrenal-derived glucocorticoids from the circulation are required. Modern approaches to this issue (transgenic mice that under or over express glucocorticoid receptor in the thymus) have yielded irreconcilably contradictory results, suggesting fundamental problems with one or more the transgenic mouse strains used. In the present study, a more direct approach was used, in which mice were adrenalectomized with or without restoration of circulating corticosterone using timed release pellets. Reversal of the increased number of thymocytes caused by adrenalectomy following restoration of physiological corticosterone concentrations would indicate that corticosterone is the major adrenal product involved in thymic homeostasis. RESULTS: A clear relationship was observed between systemic corticosterone concentration, thymus cell number, and percentage of apoptotic thymocytes. Physiological concentrations of corticosterone in adrenalectomized mice restored thymus cell number to normal values and revealed differential sensitivity of thymocyte subpopulations to physiological and stress-inducible corticosterone concentrations. CONCLUSION: This indicates that thymus-derived glucocorticoids are not sufficient to maintain normal levels of death by neglect in the thymus, but that apoptosis and possibly other mechanisms induced by physiological, non stress-induced levels of adrenal-derived corticosterone are responsible for keeping the total number of thymocytes within the normal range.

Effects on T-cell maturation and proliferation induced by lactational transfer of cyclosporine to nursing pups.

BACKGROUND: Pregnancy after allotransplantations is becoming a more common occurrence, and the immunosuppressant of choice is cyclosporine (CsA) for these patients. Consequently, the effect of CsA on prenatal and postnatal immune development and function in the infant is an increasingly important clinical issue. The purpose of this study was to evaluate the potential problems of maternal CsA exposure on neonatal T-cell maturation and proliferation after lactational transfer of CsA in an animal model. METHODS: CsA was administered daily (subcutaneous) for 20 days during lactation, beginning the day of parturition using two dose levels (15 and 25 mg/kg body weight/day) in conjunction with saline controls. RESULTS: Considerable amounts of CsA were passed to the newborn rats with neonatal blood levels equal to that of the mothers for the 25-mg/kg/day dose and 55% for the 15 mg/kg dose. There was a significant reduction in thymus/body-weight ratio and thymus cellularity for the pups born to mothers dosed at 15 or 25 mg/kg/day of CsA. The thymus from the CsA-exposed pups showed an almost complete loss of the medullary region with no apparent change in the thymic cortex. The CsA-treated mothers and their pups (15 and 25 mg/kg/day dose) had a significant increase in the percentage of CD4+CD8+ thymocytes and a significant decrease in the percentages of CD4+, CD3hi, and T-cell receptor (TCR)hi thymocyte phenotype subsets and CD4/CD8 ratios. Thymocyte proliferative responses to concanavalin A + interleukin-2 were also significantly decreased in the mother and pup after both doses of CsA. In contrast to the mothers that showed no change in splenocyte proliferative responses, their pups showed decreased responses at both the 15- and 25-mg/kg doses. All immune alterations due to CsA lactational exposure in the pups were back to control levels after 30 days of postweaning CsA cessation. CONCLUSIONS: This study clearly demonstrates that neonatal exposure to CsA via lactational transfer can cause significant alterations in T-cell maturation and inhibition of lymphoproliferative responsiveness to mitogen activation. Although the CsA blood level in human transplant patients is normally much lower, this data indicate a potential for increased risk to opportunistic infections due to altered immune components in babies exposed to long-term CsA.