Abstract
The inhibitory effects of alcohol on hepatic growth in adults raises the possibility that the liver may be involved in fetal alcohol syndrome (FAS) in infants. To test this hypothesis, pregnant Sprague-Dawley rats were fed liquid diets containing either ethanol as 36% of the total calories, or were allowed ad libitum feeding of a control liquid diet (controls) throughout pregnancy. Other dams were exposed to the ethanol diet only during the first or last half of pregnancy. Pups delivered of dams exposed to the various diets (N = 40–45/group) were killed at 1, 3, 7, and 14 days of age. In addition to brain weights, crown–rump lengths, and facial features, the following parameters of liver development were documented; liver weight, liver/body weight ratio, liver histology, hepatic ornithine decarboxylase activity (ODC), hepatic protein content, and rate of hepatic DNA synthesis (as determined by [3H]thymidine incorporation). The results revealed that pups exposed to ethanol throughout pregnancy but not ad libitum control diet pups had brain weights, crown–rump lengths, and facial features in keeping with FAS. With respect to liver development, the livers in FAS pups were consistently smaller than in the control group. However, total body weights were decreased to a greater extent, such that when corrected for body weights, the smaller livers in FAS pups only became significant on day 14 of life. Liver histology was similar in the two groups with no signs of active inflammation or fibrosis. Hepatic ODC activity was also similar, indicating no impairment in polyamine synthesis. Hepatic DNA synthesis rates were decreased in FAS pups at all time intervals. Pups delivered of dams exposed to ethanol during either the first or last half of pregnancy had results comparable to those of controls. To identify the mechanism(s) responsible for these findings, a second series of experiments was performed wherein the hepatic expression of the following factors associated with liver development were documented by northern-blot analyses; growth hormone receptor (GHr), insulin-like growth factor-I (IGF-I) and -II (IGF-II) and IGF binding proteins (IGFBPs) 1, 2, 3, and 4 mRNA on gestational days 16 and 20 and postpartum days 1 and 7. In this series, a third group of pups derived from dams in whom caloric consumption was matched to that of the ethanol-fed dams (isocaloric controls) were also studied. The results revealed no consistent differences in GHr, IGF, or IGFBP mRNA expression in the three groups. In conclusion, liver development and hepatic DNA synthesis were significantly impaired in this animal model of FAS. That impairment, however, was not associated with decreases in either polyamine synthesis or disturbances in the hepatic component of the GH/IGF/IGFBP axis.
Similar content being viewed by others
REFERENCES
Abel EL. An update on incidence of FAS: FAS is not an equal opportunity birth defect. Neurotoxicol Teratol 17:437–443, 1995
Lemoine P, Harousseau H, Borteryu JP, Menuet JC: Les enfants de parents alcooliques: Anes observée a propos de 127 cas. Quest Med 21:476–482, 1968
Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet 2:999–1001, 1973
Henderson GI, Hoyumpa AM, McClain C, Schenker S: The effects of chronic and acute alcohol administration on fetal development in the rat. Alcoholism: Clin Exp Res 3:99–106, 1979
Pullen GL, Singh SP, Snyder AK: Growth patterns of the offspring of alcohol-fed rats. Growth, Develop Aging 52:85–89, 1988
Buts J-P, Sokal EM, VanHoof F: Prenatal exposure to ethanol in rats: effects on postnatal maturation of the small intestine and liver. Pediatr Res 32:574–579, 1992
Wery I, Kaouass M, Deloyer P, Buts JP, Barbason H, Dandrifosse G: Exogenous spermine induces maturation of the liver in suckling rats. Hepatology 24:1206–1210, 1996
Holt RI, Crossey PA, Jones JS, Baker AJ, Portmann B, Miell JP: Hepatic growth hormone receptor, insulin-like growth factor I, and insulin-like growth factor-binding protein messenger RNA expression in pediatric liver disease. Hepatology 26:1600–1606, 1997
Lamas E, Zindy F, Seurin D, Guguen-Guillouzo C, Brechot C: Expression of insulin-like growth factor II and receptors for insulin-like growth factor II, insulin-like growth factor I and insulin in isolated and cultured rat hepatocytes. Hepatology 13:936–940, 1991
Diehl AM, Wells M, Brown ND, Thorgeirsson SS, Steer CJ: The effect of ethanol on polyamine synthesis during liver regeneration in rats. J Clin Invest 85:385–390, 1990
Conway S, Swain R: Somatostatin-stimulated growth hormone releasing factor secreation n vitro is modified by fetal ethanol exposure. Alcoholism: Clin Exp Res 21:703–709, 1997
Tentler JJ, LaPaglia N, Steiner J, Williams D, Casterlli M, Kelley MR, Emanuele NV, Emanuele MA: Ethanol, growth hormone and testosterone in peripubertal rats. J Endocrinol 152:477–487, 1997
Ekman AC, Vakkuri O, Ekman M, Leppaluoto J, Ruokonenn A, Knip M: Ethanol decreases nocturnal plasma levels of thyrotropin and growth hormone but not those of thyroid hormones or prolactin in man. J Clin Endocrinol Metabol 81:2627–2632, 1996
Fernstrom JD, Parkinson DE, Ebaugh AL: Acute, oral ethanol administration suppresses episodic growth hormone secretion in the male rat. Endocrinology 136:1059–1064, 1995
Badger TM, Ronis MJJ, Lumpkin CK, Valentine CR, Shahare M, Irby D, Huang J, Mercado C, Thomas P, Ingelman-Sundberg M, Crouch J: Effects of chronic ethanol on growth hormone secretion and hepatic cytochrome P450 isozymes of the rat. J Pharmacol Exper Ther 264:438–447, 1993
Soszynski PA, Frohman LA: Inhibitory effects of ethanol on the growth hormone (GH)-releasing hormone—GH—insulinlike growth factor-I axis in the rat. Endocrinology 131:2603–2608, 1992
Emanuele MA, Tentler JJ, Kristeins L, Emanuele NV, Lawrence A, Kelley MR: The effect of “binge” ethanol exposure on growth hormone and prolactin gene expression and secretion. Endocrinology 131:2077–2082, 1992
Breese CR, Sonntag WE: Effect of ethanol on plasma and hepatic insulin-like growth factor regulation in pregnant rats. Alcoholism: Clin Exp Res 19:867–873, 1995
Hochberg Z, Phillip M, Youdim MBH, Amit T. Regulation of the growth hormone (GH) receptor and GH-binding protein by GH pulsatility. Metabolism 42:1617–1623, 1993
Sonntag WE, Body RL: Chronic ethanol feeding inhibits plasma levels of insulin-like growth factor-I. Life Sci 43:1325—1330, 1988 21. Xu X, Ingram RL, Sonntag WE: Ethanol suppresses growth hormone-mediated cellular responses in liver slices. Alcohol Clin Exp Res 19:1246–1251, 1995
Mauceri HJ, Lee WH, Conway S: Effect of ethanol on insulin-like growth factor II release from fetal organs. Alcohol Clin Exp Res 18:35–41, 1994
Fatayerji N, Engelmann GL, Myers T, Handa RJ: In utero exposure to ethanol alters mRNA for insulin-like growth factors and insulin-like growth factor binding proteins in placenta and lung of fetal rats. Alcohol Clin Exp Res 20:94–100, 1996
McCann PP, Tardif C, Mamont PS, Schuber F: Biphasic induction of ornithine decarboxylase and putrescine levels in growing HTC cells. Biochem Biophys Res Commun 64:336–341, 1975
Hartree EF. Determination of protein: A modification of the Lowry method that gives a linear photometric response. Anal Biochem 48:422–427, 1972
Luk GD: Essential role of polyamine metabolism in hepatic regeneration. Gastroenterology 90:1261–1267, 1986
Vytasek R: A sensitive fluorometric assay for the determination of DNA. Anal Biochem 120:243–248, 1982
Sambrook J, Fitsch EF, Maniatis T. (1989) Molecular Cloning, 2nd ed. Cold Spring Harbor, New York, Cold Spring Harbor Laboratory Press.
Bucher NLR: Regeneration of mammalian liver. In International Review of Cytology. GH Bourne, JF Danielli (eds). New York, Academic Press, 1963, pp. 245–294.
Assy N and Minuk GY: Liver regeneration: methods for monitoring and their applications. J Hepatol 26:945–952, 1997
Balduini W, Reno F, Costa LG, Cattabeni F: Developmental neurotoxicity of ethanol: further evidence for an involvement of a muscarinic receptor-stimulated phosphoinositide hydrolysis. Eur J Pharmacol 266:283–289, 1994
Singh SP, Snyder AK, Pullen GL: Fetal alcohol syndrome: glucose and liver metabolism in term fetus neonates. Alcoholism: Clin Exp Res 10:54–58, 1986
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Meyers, A., Gong, Y., Zhang, M. et al. Liver Development in a Rat Model of Fetal Alcohol Syndrome. Dig Dis Sci 47, 767–772 (2002). https://doi.org/10.1023/A:1014735932272
Issue Date:
DOI: https://doi.org/10.1023/A:1014735932272