Sporidesmin-induced mortality and histological lesions in mouse lines divergently selected for response to toxins in endophyte-infected fescue.

For eight generations, mouse lines were selected for smaller or larger reduction in postweaning gain from endophyte-infected fescue seed in the diet. After five generations in which there was no further selection for divergence in response to fescue toxicosis, the current experiment was conducted to determine whether resistant (R) and susceptible (S) lines differed in response to the mycotoxin sporidesmin (SPD). At approximately 8 wk of age, R and S mice that had never consumed endophyte-infected fescue seed were randomly assigned (five to seven per line x sex x SPD dose subclass) to receive dimethyl sulfoxide (DMSO) carrier or 10, 20, 30, or 40 mg/kg SPD by oral gavage. At death or euthanasia 14 d after treatment, livers and kidneys were collected for histological examination. Mice receiving 40 mg/kg SPD died sooner than mice receiving 30 mg/kg (63 vs 134 h; P = .02), but there was no line or line x dose interaction effect for time to death. Within those mice, neither line, dose, nor their interaction influenced liver weight or liver weight as a proportion of body weight. The R mice were more resistant to SPD than S mice; LD50 values were 23.6 and 31.8 mg/kg for the S and R lines, respectively (P < .05). Sporidesmin caused dose-related liver and kidney lesions in both lines. Selection lines did not differ significantly in the incidence of infarcts of hepatic lobules. However, at 30 and 40 mg/kg SPD doses, severity of this lesion was higher in affected S than in affected R mice. At the higher SPD doses, there also was a greater incidence of hepatic subacute cholangitis in S mice than in R mice. Foci of acute tubular necrosis were found in kidneys of mice receiving 20, 30, or 40 mg/kg SPD, with no protection against these lesions in the R line. Foci of tubular basophilia (indicative of tubular regeneration) were present in all line x dose subgroups, but incidence was not SPD dose-dependent in either line. In summary, divergent selection for weight gain response to ingestion of endophyte-infected fescue seed resulted in a favorable correlated response in survival following exposure to a chemically distinct toxin. It may be possible therefore, to select livestock populations for simultaneous resistance to a variety of toxins.