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

Abstract

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.

Sleep time following anesthesia in mouse lines selected for resistance or susceptibility to fescue toxicosis

“…After eight generations of selection, the lines differed in the impact of an E+ diet on growth, and R mice had higher hepatic Phase II enzyme activities than S mice (Hohenboken and Blodgett, 1997). Reproduction in the S line was more severely depressed by an E+ diet than was reproduction in the R line (Wagner et al, 2000), and R mice had higher resistance than S mice to the mycotoxin, sporidesmin (Hohenboken et al, 2000).…”

Response to intensity of reproduction in mouse lines resistant or susceptible to fescue toxicosis

“…2000). After six generations of relaxed selection, R males were more resistant to sporidesmin toxin than S males (Hohenboken et al. 2000).…”

Review of genetic studies of susceptibility to facial eczema in sheep and dairy cattle

“…Genetic differences in response to the challenge among sire groups of cattle have been reported (Lipsey et al 1992) and breed differences in weight gain have been recorded in affected cattle in Arkansas (Morrison et al 1988). Related studies of ergovaline susceptibility in mice have been carried out, where heritable differences in tolerance to ergovaline in the diet were found among selection lines (Hohenboken and Blodgett, 1997); following an artificial challenge with sporidesmin in the selected lines, some of the genetic variation among lines for ergovaline tolerance was found to be in common with that for resistance to FE (Hohenboken et al 2000). This suggests that some genes for the detoxification of ergovaline and sporidesmin may be in common, as was the case of lolitrem and sporidesmin, described earlier.…”