Effects of oral administration of manganese on the kidneys and urinary bladder of Sprague-Dawley rats.

The purpose of this study was to investigate the effect of oral administration of manganese acetate on the kidneys and urinary bladder of Sprague-Dawley (SD) rats. Male and female SD rats (150 to 175 g), 6 weeks old, were administered varying doses of manganese acetate for 63 days by oral gavage. At the end of 63 days, 50% of the animals were sacrificed and kidney tissue was isolated and fixed for histopathological studies (study A). The remaining 50% were cross-mated and dosing ceased. Animals were sacrificed after 2 weeks (study B). Male treated animals were noted to have viscous, gritty urine in the urinary bladder, and the high-dose groups had urinary bladder stones (uroliths). Histopathologically, the most striking lesions were observed in the kidneys and prostate glands of male animals. Mild-to-moderate tubulointerstitial nephritis with tubular proteineous and glomerulosclerosis was observed in animals of all treatment groups. Urolithiasis in the urinary bladder was confirmed in 33% to 66% of treated animals. Female animals did not show a significant difference above controls in renal tissues. Results of this study suggest that male rats are more sensitive to the effects of high levels of manganese given orally than female rats and that the genitourinary structures represent target organs of toxicity.

Role of the maternal acute phase response and tumor necrosis factor alpha in the developmental toxicity of lipopolysaccharide in the CD-1 mouse.

The acute phase response (APR) functions to reset metabolic homeostasis following infectious, toxic, or traumatic insult. TNF-alpha, a putative mediator of the APR, has been associated with fetal death in rodents and preterm labor and delivery in humans. We hypothesized that physiologic changes associated with the maternal APR may play a role in adverse embryo/fetal outcome. Pregnant CD-1 mice injected i.p. with lipopolysaccharide (LPS), a model inducer of the APR, on gestation day (gd) 9 showed a dose-related increase in embryo death on gd 10. Histology indicated placental infarct and necrosis. Maternal serum TNF-alpha levels, measured by ELISA following administration of 0.05 mg/kg LPS on gd 9, were found to increase significantly and peak within 1 to 1.5 h. Pretreatment with 0.01 mg/kg LPS on gd 8 ameliorated embryotoxicity of the 0.05 mg/kg LPS treatment on gd 9 and also eliminated the increase in serum TNF-alpha. Direct LPS exposure in whole embryo culture was nontoxic. These data support a maternally mediated mechanism of LPS embryolethality, and suggest that TNF-alpha may be an important mediator of this developmental toxicity.