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Trifluoroacetylated adducts in spermatozoa, testes, liver and plasma and CYP2E1 induction in rats after subchronic inhalatory exposure to halothane. Oropeza-Hernández Luis F,Quintanilla-Vega Betzabet,Reyes-Mejía Raul A,Serrano Carmen J,García-Latorre Ethel A,Dekant Wolfgang,Manno Maurizio,Albores Arnulfo Toxicology letters The induction of cytochrome P450 (CYP) 2E1 in testes and liver and the presence of trifluoroacetylated (TFA) adducts in spermatozoa, testes, liver and plasma were investigated in rats subchronically exposed by inhalation to halothane (15 ppm/4 h/day/5 days/week/9 weeks). After halothane exposure, p-nitrophenol hydroxylase (p-NPH) activity increased 3.2-fold and CYP2E1 apo-protein content 7-fold in testes, whereas in liver, p-NPH increased 2.3-fold and CYP2E1 apoprotein content 1.4-fold. These results suggest a differential inductive effect of halothane on CYP2E1 in these tissues. Moreover, TFA adducts were present in microsomes of testis and liver and in plasma of halothane-treated rats. The immunoblot analysis of testicular microsomes showed two intense TFA protein bands of 63 and 59 kDa, whereas in liver three intense bands of 100, 76 and 63 kDa were observed. Bands of similar molecular weights to those observed in liver were detected in the plasma of halothane-treated animals. In addition, TFA adducts were detected by immunofluorescence in spermatozoa, probably in the acrosome and/or perinuclear theca region, and in the distal tail of spermatozoa. The increase in CYP2E1 apoprotein and p-NPH activity observed in testis and liver microsomes suggests that halothane induces its own biotransformation both hepatically and extrahepatically and in addition, that the nature of the TFA adducts will depend on the proteins present in each tissue. Also, the presence of TFA adducts in spermatozoa may result from the activation of halothane in the reproductive tract. The detailed mechanism of TFA adduct formation and its consequences on the spermatozoa function remain to be fully clarified.
Trifluoroethanol and its oxidative metabolites: comparison of in vivo and in vitro effects in rat testis. Lloyd S C,Blackburn D M,Foster P M Toxicology and applied pharmacology Trifluoroethanol (TFE) and trifluoroacetaldehyde (TFALD) produced a reduction in testis weight 3 days after a single oral dose of 10 mg/kg. In contrast, administration of trifluoroacetic acid (TFAA) caused no observable testicular effects. Reduction in testis weight was accompanied by morphological changes, involving specific damage to pachytene and dividing spermatocytes, and round spermatids. In an in vitro Sertoli/germ cell co-culture system, only TFALD was found to produce dose-related effects at concentrations of 10(-3) and 10(-4) M. There was increased germ cell loss from the cultures, particularly loss of pachytene and dividing spermatocytes, accompanied by leakage of the pachytene spermatocyte marker enzyme, lactate dehydrogenase-X. TFE and TFAA did not produce these effects in the culture system at concentrations equimolar with TFALD. These results suggest that TFALD may play a critical role in the development of the testis lesion seen with TFE in vivo. The effects seen both in vivo and in vitro were remarkably similar to those previously reported for another substituted alcohol and its metabolites, ethylene glycol monomethyl ether. It is postulated that the two series of compounds may have a similar mode of action on rat testis.
Mammalian toxicity of trifluoroacetate and assessment of human health risks due to environmental exposures. Archives of toxicology While trifluoroacetic acid has limited technical uses, the highly water-soluble trifluoroacetate (TFA) is reported to be present in water bodies at low concentrations. Most of the TFA in the environment is discussed to arise from natural processes, but also with the contribution from decomposition of environmental chemicals. The presence of TFA may result in human exposures. For hazard and risk assessment, the mammalian toxicity of TFA and human exposures are reviewed to assess the margin of exposures (MoE). The potential of TFA to induce acute toxicity is very low and oral repeated dose studies in rats have identified the liver as the target organ with mild liver hypertrophy as the lead effect. Biomarker analyses indicate that TFA is a weak peroxisome proliferator in rats. TFA administered to rats did not induce adverse effects in an extended one-generation study and in a developmental toxicity study or induce genotoxic responses. Based on recent levels of TFA in water and diet, MoEs for human exposures to TFA are well above 100 and do not indicate health risks. 10.1007/s00204-023-03454-y
Postnatal hepatic and renal consequences of in utero exposure to halothane or its oxidative metabolite trifluoroacetic acid in the rat. Saillenfait A M,Roure M B,Ban M,Gallissot F,Langonné I,Sabaté J P,Bonnet P Journal of applied toxicology : JAT In utero exposure of rats to low levels of the anaesthetic halothane has been reported to produce ultrastructural changes in the liver and kidney at birth. The current study examined the postnatal functional capacities of the liver and the kidney following prenatal exposure to halothane. Halothane or its oxidative metabolite trifluoroacetic acid (TFAA) were given to Sprague-Dawley rats on gestational days 10-20. Halothane was administered by inhalation at concentration of 50 or 500 ppm 6 h-1 day-1, and TFAA was administered by gavage at doses of 75 or 150 mg kg-1 day-1. The exposed offsprings were examined on postnatal days 3, 12 or 49 for hepatic and renal biochemistry and/or function through measurements of several serum and urinary parameters. Neither halothane nor TFAA treatments had statistically significant effect on litter size, neonatal survival or postnatal growth. Both prenatal halothane and TFAA exposure produced changes in liver biochemistry of newborns, as indicated by significant increases in the serum activities of glutamate dehydrogenase and aspartate aminotransferase. In addition, TFAA caused a functional deficit of the proximal tubule in newborns, as evidenced by the significant increase in the urinary excretion of beta 2-microglobulin. However, these hepatic and renal alterations were restricted to the early postnatal period and were no longer observed by postnatal day 49. It is concluded that prenatal exposure to relatively low levels of halothane can cause slight and transient changes in the neonatal rat liver.