Strain-dependent responses of subacute exposure to trichloroethylene in a multi-strain panel of mice: An oxidative metabolite and the liver effects

Abstract

Trichloroethylene (TCE), a common industrial material and environmental contaminant, is carcinogenic in kidney to human and can induce liver toxicity in mice

however, there were a few of evidence on liver toxicity in humans. Moreover, recent few studies indicated diverse variability of TCE metabolism and its toxicity in population-based mouse model, but there are still lots of knowledge gaps on subject variability of the health effects. The aim of this study was to identify more susceptible strains and their metabolic determinants and features of liver toxicity using multi-strain of mice. Thus, we measured dose-dependent metabolism and determined liver toxicity of TCE in seven strains of mice. 129S1/SvImJ, A/J, B6C3F1, BALB/cJ, C3H/HeJ, C57BL/6J and DBA/2J showing diverse genetic background and phenotypes among strains but homogenous traits within a strain were selected and TCE was administered with oral gavage for four weeks at 0, 10, 100 and 1000 mg/kg/day (4 groups per strain

3 to 5 mice per group). Serum trichloroacetic acid (TCA) as an oxidative metabolite of TCE and various markers of liver weight gain and toxicity were measured at 24 hours after the last dose including the proliferating cellular nuclear antigen-labeling index (PCNA-LI) of liver tissues. There were significant dose- and strain-dependent differences in levels of serum TCA and liver weight gain after TCE exposure for four weeks (p < 0.05). Fold change of TCA to control group increased by dosage and some strains were distinguishable

however, those trends for liver weight gain were not maintained in some strains. While DBA/2 and A/J produced TCA noticeably more than others, BALB/c, 129S1/SvImJ and A/J yielded more liver-weight gain by dosage. C57BL/6J was not markedly increase in both TCA and liver weight compared with the others. In general, TCE metabolism (TCA production) had strong correlation with liver-weight gains (=0.52, p<0.05)

however, not all higher TCA producing strains were higher liver-weight gaining group. Both high liver-weight gaining strains (BALB/c, 129S1/SvImJ and A/J) and a low strain (C57BL/6J) showed marginal correlation between PCNA-LI and liver weight gain (ρ=0.36, p=0.068), but there were significant increases of PCNA-LI in 129S1/SvlmJ and C57BL/6J at TCE 1000 mg/kg relative to control (p < 0.05). Cell proliferation (PCNA-LI) could explain high liver-weight gain by dose in 129S1/SvImJ not A/J

interestingly, there were significant increase in PCNA in a low liver-weight gaining strain (C57BL/6J). There was no significant difference of levels of liver injury marker among strains by dosage and necrosis was not detected in all. Suggestively, although it was confirmed that TCE metabolism attributed to liver weigh gain, strains with high metabolism were not same as in the more liver-weight gain. Further studies are required for causes and the modes of action of the liver-weight gain, but cell proliferation could be explanatory of it in 129S1/SvImJ.