Acute liver failure (ALF) is a clinical syndrome with high mortality rate, resulting from widespread hepatocyte damage. Its pathophysiological background is still poorly understood and preclinical studies evaluating pathophysiology and new potential therapeutic measures are needed. The model of ALF induced by administration of thioacetamide (TAA) in Lewis rats is recommended as optimal; however, the limitation of previous studies was that they were performed predominantly in male rats. In view of the growing recognition that sex as a biological variable should be taken into consideration in preclinical research, we examined its role in the development of TAA-induced ALF in Lewis rats. We found that, first, intact male Lewis rats showed lower survival rate than their female counterparts, due to augmented liver injury documented by higher plasma ammonia, and bilirubin levels and alanine aminotransferase activity. Second, in female rats castration did not alter the course of TAA-induced ALF whereas in the male gonadectomy improved the survival rate and attenuated liver injury, reducing it to levels observed in their female counterparts. In conclusion, we found that Lewis rats show a remarkable sexual dimorphism with respect to TAA-induced ALF, and male rats display dramatically poorer prognosis as compared with the females. We showed that testosterone is responsible for the deterioration of the course of TAA-induced ALF in male rats. In most general terms, our findings indicate that in the preclinical studies of the pathophysiology and treatment of ALF (at least of the TAA-induced form) the sex-linked differences should be seriously considered.

Department of Surgery 2nd Faculty of Medicine Charles University and Central Military Hospital Prague Czech Republic

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AKHTAR T, SHEIKH N. An overview of thioacetamide-induced hepatotoxicity. Toxin Rev. 2016;32:43–46. doi: 10.3109/15569543.2013.805144. DOI

AMACHER DE. Female gender as a susceptibility factor for drug-induced liver injury. Hum Exp Toxicol. 2014;68:76–84. doi: 10.1177/0960327113512860. PubMed DOI

BERNAL W, HYYRYLAINEN A, GERA A, AUDIMOOLAM VK, McPHAIL MJ, AUZINGENR G, RELA M, HEATON N, O’GRADY JG, WENDON J, WILLIAMS R. Lessons from look-back in acute liver failure? A single center experience of 3300 patients. J Hepatol. 2013;59:74–80. doi: 10.1016/j.jhep.2013.02.010. PubMed DOI

BIZZARO D, CRESCENCI M, Di LIDDO R, ARCIDIACONO D, CAPPON A, BERTALO T, AMODIO V, TASSO A, STEFANI A, BERTAZO V, GERMANI G, FRASSON C, BASSO G, PARNIGOTTO P, ALISON MR, BURRA P, CONCONI MT, RUSSSO FP. Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury. Clin Sci. 2017;132:255–272. doi: 10.1042/cs20171260. PubMed DOI

BUTTERWORTH RF, NORENBERG MD, FELIPO V, FERENCI P, ALBRECTH J, BLEI AT. Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int. 2009;29:783–788. doi: 10.1111/j.1478-3231.2009.02034.x. PubMed DOI

BUZZETTI E, PARIKH PM, GERUSSI A, TSOCHATZIS E. Gender differences in liver disease and the drug-dose gender gap. Pharmacol Res. 2017;120:97–108. doi: 10.1016/j.phrs.2017.03.014. PubMed DOI

ČERVENKA L, ŠKAROUPKOVÁ P, KOMPANOWSKA-JEZIERSKA E, SADOWSKI J. Sex-linked differences in the course of chronic kidney disease and congestive heart failure: a study in 5/6 nephrectomized Ren-2 transgenic hypertensive rats with volume overload induced using aorto-caval fistula. Clin Exp Pharmacol Physiol. 2016;43:883–895. doi: 10.1111/1440-1681.12619. PubMed DOI

DOCHERTY JR, STANFORD SC, PANATTIERI RA, ALEXANDER SPH, CIRINO G, GEORGE CH, HOYER D, IZZO AA, JI Y, SOBEY CG, STANLEY P, STEFANSKA G, TEIXEIRA M, AHLUWALIA A. Sex: a change in our guidelines to authors to ensure that this is no longer an ignored experimental variable. Br J Pharmacol. 2019;176:4081–4086. doi: 10.1111/bph.14761. PubMed DOI PMC

DUCHESNE A, TANNENBAUM C, EINSTEIN G. Funding agency mechanisms to increase sex and gender analysis. Lancet. 2017;289:699–700. doi: 10.1016/s0140-6736(17)30343-4. PubMed DOI

FYFE B, ZALDANA F, LIU C. The pathology of acute liver failure. Clin Liver Dis. 2018;22:257–268. doi: 10.1016/j.cld.2018.01.003. PubMed DOI

GOCHFELD M. Framework for gender differences in human and animal toxicology. Environ Res. 2007;104:4–21. doi: 10.1016/j.envres.2005.12.005. PubMed DOI

GROSSMANN M, WIERMAN ME, ANGUS P, HANDELSMAN DJ. Reproductive endocrinology of nonalcoholic fatty liver disease. Endocr Rev. 2019;40:417–446. doi: 10.1210/er.2018-00158. PubMed DOI

GUSTAFSSON JA, MODE A, NORSTEDT G, SKETT P. Sex steroid induced changes in hepatic enzymes. Annu Rev Physiol. 1983;45:51–60. doi: 10.1146/annurev.ph.45.030183.000411. PubMed DOI

HAJOVSKY H, HU G, KOEN Y, SARMA D, CUI W, MOORE DS, STAUDINGER JL, HANZLIK RP. Metabolism and toxicity of thioacetamide and thioacetamide S-oxide in rat hepatocytes. Chem Res Toxicol. 2012;25:1955–1963. doi: 10.1021/tx3002719. PubMed DOI PMC

KALA P, ČERVENKA L, ŠKAROUPKOVÁ P, TÁBORSKÝ M, KOMPANOVSKA-JEZIERSKA E, SADOWSKI J. Sex-linked differences in the mortality in Ren-2 transgenic hypertensive rats with aorto-caval fistula: effects of treatment with angiotensin converting enzyme alone and combined with inhibitor of soluble epoxide hydrolase. Physiol Res. 2019;68:589–601. doi: 10.33549/physiolres.934094. PubMed DOI

KOBLIHOVÁ E, MRÁZOVÁ I, VERNEROVÁ Z, RYSKA M. Acute liver failure induced by thioacetamide: selection of optimal dosage in Wistar and Lewis rats. Physiol Res. 2014;63:491–503. doi: 10.33549/physiolres.932690. PubMed DOI

KOBLIHOVÁ E, LUKŠAN O, MRÁZOVÁ I, RYSKA M, ČERVENKA L. Hepatocyte transplantation attenuates the course of acute liver failure induced by thioacetamide in Lewis rats. Physiol Res. 2015;64:689–700. doi: 10.33549/physiolres.932914. PubMed DOI

KOBLIHOVÁ E, MRÁZOVÁ I, VAŇOURKOVÁ Z, MAXOVÁ H, KIKERLOVÁ S, HUSKOVÁ Z, RYSKA M, FRONĚK J, VERNEROVÁ Z. Pharmacological stimulation of Wnt/β-catenin signaling pathway attenuates the course of thioacetamide-induced acute liver failure. Physiol Res. 2020;69:113–126. doi: 10.33549/physiolres.934071. PubMed DOI PMC

KOEN YM, SARMA D, HAJOVSKY H, GALEVA NA, WILIAMS TD, STAUDINGER JL, HANZLIK RP. Protein targets of thioacetamide metabolites in rat hepatocytes. Chem Res Toxicol. 2013;26:564–574. doi: 10.1021/tx400001x. PubMed DOI PMC

LEE KS. Sex as an important biological variable in biomedical research. BMP Rep. 2018;51:167–173. doi: 10.5483/bmbrep.2018.51.4.034. PubMed DOI PMC

LEE YH, SON JY, KIM KS, PARK YJ, KIM HR, PARK JH, KIM KB, LEE KY, KANG KW, KIM IS, KACEW S, LEE BM, KIM HS. Estrogen deficiency potentiates thioacetamide-induced hepatic fibrosis in Sprague-Dawley rats. Int J Mol Sci. 2019;20:3709. doi: 10.3390/ijms20153709. PubMed DOI PMC

LIMA LCD, MIRANDA AS, FERREIRA RN, RACHID MA, SIMOES E, SILVA AC. Hepatic encephalopathy: lessons from preclinical studies. Word J Hepatol. 2019;11:173–185. doi: 10.4254/wjh.v11.i2.0000. PubMed DOI PMC

MANNON EC, RAY SC, RYAN MJ, SULLIVAN JC. Does sex matter?: an update on the implementation of sex as a biological variable in research. Am J Physiol Renal Physiol. 2020;318:F329–F331. doi: 10.1152/ajprenal.00575.2019. PubMed DOI PMC

MARCOS R, CORREIA-GOMES C, MIRANDA H, CARNEIRO F. Liver gender dimorphism – insights from quantitative morphology. Histol Histopathol. 2015;30:1431–1437. doi: 10.14670/HH-11-648. PubMed DOI

MENNECOZZI M, LADESMANN B, PALOSAARI T, HARRIS G, WHELAN M. Sex differences in liver toxicity – do female and male human primary hepatocytes react differently to toxicants in vitro? PLoS One. 2015;10:e0122786. doi: 10.1371/journal.pone.0122786. PubMed DOI PMC

MILLER MA. Gender-based differences in the toxicity of pharmaceuticals: the Food and Drug Administration’s perspective. Int J Toxicol. 2001;20:149–152. doi: 10.1080/109158101317097728. PubMed DOI

NATIONAL INSTITUTES OF HEALTH OFFICE OF EXTRAMURAL RESEARCH. Consideration of sex as a biological variable in NIH-funded research. Available: https://orwh.od.nih.gov/sites/orwh/files/docs/NOT-OD-15-102_Guidance.pdf.

OSTADAL B, NETUKA I, MALY J, BESIK J, OSTADALOVA I. Gender differences in cardiac ischemic injury and protection – experimental aspects. Exp Biol Med (Maywood) 2009;234:1011–1019. doi: 10.3181/0812-mr-362. PubMed DOI

OSTAPOWICZ G, FONTANA RJ, SCHODT FV, LARSON A, DAVERN TJ, HAN SH, McCASHLAND TM, SHAKIL AO, HAY JE, HYNAN L, CRIPPIN JS, BLEI AT, SAUMEL G, REISCH J, LEE WM US ACUTE LIVER FAILURE GROUP. Results from a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947–954. doi: 10.7326/0003-4819-137-12-200212170-00007. PubMed DOI

PATEL P, OKORNKWO N, PYRSOPOULOS NT. Future approaches and therapeutic modalities for acute liver failure. Clin Liver Dis. 2018;22:419–427. doi: 10.1016/j.cld.2018.01.011. PubMed DOI

REGITZ-ZAGROSEK V, KARARIGAS G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev. 2017;97:1–37. doi: 10.1152/physrev.00021.2015. PubMed DOI

REUBEN A, TILLMAN H, FONTANA RJ, DAVERN T, McGUIRE B, STRAVITZ RT, DRUKALSKI V, LARSON AM, LIOU I, FIX O, SCHILSKY M, McCASHLAND T, HAY JE, MURAY N, SHAIKH OS, GANGER D, ZAMAN A, HAN SB, CHUNG RT, SMITH A, ET AL. Outcomes in adults with acute liver failure between 1998 and 2013: and observational cohort study. Ann Intern Med. 2016;164:724–732. doi: 10.7326/m15-2211. PubMed DOI PMC

RUBIN JB, HAMMED B, GOTTFRIED M, LEE W, SARKAR M ACUTE LIVER FAILURE STUDY GROUP. Acetaminophen-induced acute liver failure is more common and more severe in women. Clin Gastroenterol Hepatol. 2018;16:936–946. doi: 10.1016/j.cgh.2017.11.042. PubMed DOI PMC

SCHOTTEN D, TREBLICKA J, LIEDTKE C, WEISKIRCHEN R. The carbon tetrachloride model in mice. Lab Anim. 2015;49:4–11. doi: 10.1177/0023677215571192. PubMed DOI

SINCLAIR M, GOW PJ, GROSSMANN M, SHANNON A, HOERMANN R, ANGUS PW. Low serum testosterone is associated with adverse outcome in men with cirrhosis independent of the model of end-stage liver disease score. Liver Transpl. 2016;22:1482–1490. doi: 10.1002/lt.24607. PubMed DOI

SOLDIN OP, CHUNG SH, MATTISON DR. Sex differences in drug disposition. J Biomed Biotechnol. 2011;187103:1–14. PubMed PMC

STRAFACE E, GAMBARDELLA L, BRANDANI M, MALORNI W. Sex differences at cellular level: “cells have a sex”. Handb Exp Pharmacol. 2012;214:49–65. doi: 10.1007/978-3-642-30726-3_3. PubMed DOI

STRAVITZ RT, LEE WM. Acute liver failure. Lancet. 2019;394:869–881. doi: 10.1016/S0140-6736(19)31894-X. PubMed DOI PMC

SUCHY FJ. Hepatobiliary function. In: BORON WF, BOULPAEP EL, editors. Medical Physiology. 2nd edition. Saunders Elsevier; Philadelphia, PA, USA: 2009. pp. 980–1008.

SUTTI S, TACKE F. Liver inflammation and regeneration in drug-induced liver injury: sex matters! Clin Sci. 2018;132:609–613. doi: 10.1042/cs20171313. PubMed DOI

TRAISH AM. Health risk associated with long-term finasteride and dutasteride use: it’s time to sound the alarm. World J Mens Health. 38:323–337. doi: 10.5534/wjmh.200012. PubMed DOI PMC

TSUKAMOTO I, KOJO S. The sex difference in the regulation of liver regeneration after partial hepatectomy in the rat. Biochim Biophys Acta. 1990;1033:287–290. doi: 10.1016/0304-4165(90)90135-j. PubMed DOI

TUÑÓN MJ, ALVAREZ M, CULEBRAS JM, GONZÁLES-GALLEGO J. An overview of animal models for investigating the pathogenesis and therapeutical strategies in acute hepatic failure. Word J Gastroenterol. 2009;15:3086–3098. doi: 10.3748/wjg.15.3086. PubMed DOI PMC

VANĚČKOVÁ I, HUSKOVÁ Z, VAŇOURKOVÁ Z, ČERVENKA L. Castration has antihypertensive and organoprotective effects in male but not in female heterozygous Ren-2 rats. Kidney Blood Press Res. 2011;34:46–52. doi: 10.1159/000322618. PubMed DOI

WAXMAN DJ, HOLLOWAY MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol. 2009;76:215–228. doi: 10.1124/mol.109.056705. PubMed DOI PMC

WAXMAN DJ, O’CONNOR C. Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol. 2006;20:2613–2629. doi: 10.1210/me.2006-0007. PubMed DOI

WEILER N, SCHLOTMANN A, SCHNITZBAUER AA, ZEUZEM S, WELKER MV. The epidemiology of acute liver failure. Dtsch Arztebl Int. 2020;117:43–50. doi: 10.3238/arztebl.2020.0043. PubMed DOI PMC

WHO. What do we mean by “sex” and “gender”? Available: http://www.who.int/gender/whatisgender/en/

ZUCKER I, BEERY AK. Studying sex as a biological variable: is a new day dawning? J Womens Health (Larchmt) 2019;28:1–2. doi: 10.1089/jwh.2018.7598. PubMed DOI

Sex-Linked Differences in Cardiac Atrophy After Heterotopic Heart Transplantation: No Direct Relation to the Actions of Sex Steroid Hormones

Sex-Linked Differences in Cardiac Atrophy After Mechanical Unloading Induced by Heterotopic Heart Transplantation

Sex Difference in Plasma Deoxyribonuclease Activity in Rats