Original article| Volume 124, ISSUE 2, P183-192, August 1994

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Insulin-like growth factors (IGF-I and IGF-II), IGF-binding proteins, and IGF gene expression in the offspring of ethanol-fed rats

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      Insulin-like growth factors I and II (IGF-I, IGF-II) and IGF-binding proteins (IGFBPs) are important modulators of fetal growth. Fetal growth retardation is a major component of the fetal alcohol syndrome, which is associated with maternal alcoholism. This study examined the relationship of IGF-system components to growth retardation induced by ethanol in fetuses of rats fed equicaloric liquid diets (AF, ad libitum-fed controls; PF, pair-fed controls; EF, ethanol-fed) during gestation. The gene expression of IGF-I and IGF-II in fetal liver and the concentration of IGFs and IGFBPs in serum and liver were determined. The mean weight of EF fetuses was 13% and 16% less (p < 0.01) than that of PF and AF offspring, respectively. The serum concentration of IGF-I was decreased (p < 0.05) by 17% and 22% in EF as compared with PF and AF fetuses. Fetal body weight showed positive correlations with fetal serum IGF-I and IGF-II (r = 0.566, p < 0.01, and r = 0.412, p < 0.05, respectively). Fetal liver weight correlated with fetal liver IGF-I and IGF-II, with r values of 0.514 (p < 0.01) and 0.493 (p < 0.01). Hepatic IGF-II mRNA abundance was decreased (p < 0.05) by 27% and 26% in EF as compared with PF and AF offspring. The level of fetal liver IGF-I mRNA expression was low but was also reduced comparably in EF pups. IGFBP content in EF fetal serum was increased (p < 0.05 vs AF), and correlated negatively with fetal body weight (r = −0.505, p < 0.01). The diminished IGF-I and IGF-II gene expression and the reduced tissue and circulating peptide levels, along with a converse change in serum IGFBP abundance, may have a role in the pathogenesis of fetal alcohol syndrome.


      AF (control group given free access to food), EDTA (ethylenediamine tetraacetic acid), EF (ethanol-fed group), IGF (insulin-like growth factor), IGFBP (IGF binding protein), PF (pair-fed group)
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        • Abel EL
        • Sokol RJ
        A revised conservative estimate of the incidence of FAS and its economic impact.
        Alcohol Clin Exp Res. 1991; 15: 514-524
        • Ernhart CB
        • Sokol RJ
        • Martier S
        • et al.
        Alcohol teratogenicity in the human: a detailed assessment of specificity, critical period, and threshold.
        Am J Obstet Gynecol. 1987; 156: 33-39
        • Hoyseth KS
        • Jones PJ
        Ethanol induced teratogenesis: characterization, mechanisms and diagnostic approaches.
        Life Sci. 1989; 44: 643-659
        • Sara VR
        • Hall K
        Insulin-like growth factors and their binding proteins.
        Physiol Rev. 1990; 70: 591-614
        • Daughaday WH
        • Rotwein P
        Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations.
        Endocrine Rev. 1989; 10: 68-91
        • Clemmons DR
        • Underwood LE
        Nutritional regulation of IGF-I and IGF binding proteins.
        Ann Rev Nutr. 1991; 11: 393-412
        • Straus DS
        • Ooi GT
        • Orlowski CC
        • Rechler MM
        Expression of the genes for insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins-1 and -2 in fetal rat under conditions of intrauterine growth retardation caused by maternal fasting.
        Endocrinology. 1991; 128: 518-525
        • Straus DS
        • Takemoto CD
        Specific decrease in liver insulin-like growth factor-I and brain insulin-like growth factor-II gene expression in energy-restricted rats.
        J Nutr. 1991; 121: 1979-1986
        • Vileisis RA
        • D'Ercole AJ
        Tissue and serum concentrations of somatomedin-C/insulin-like growth factor I in fetal rats made growth retarded by uterine artery ligation.
        Pediatr Res. 1986; 20: 126-130
        • Price WA
        • Stiles AD
        • Moats-Staats BM
        • D'Ercole AJ
        Gene expression of insulin-like growth factors, the type I IGF receptor, and IGF-binding proteins in dexamethasone-induced fetal growth retardation.
        Endocrinology. 1992; 130: 1424-1432
        • Singh SP
        • Snyder AK
        • Singh SK
        Effect of ethanol consumption on maternal and fetal carbohydrate metabolism.
        J Lab Clin Med. 1984; 105: 176-184
        • Witek-Janusek L
        Maternal ethanol ingestion: effect on maternal and neonatal glucose balance.
        Am J Physiol. 1986; 251: E178-E184
        • Snyder AK
        • Singh SP
        • Pullen GL
        Ethanol-induced intrauterine growth retardation: Correlation with placental glucose transfer.
        Alcohol Clin Exp Res. 1986; 10: 167-170
        • Singh SP
        • Snyder AK
        • Pullen GL
        Maternal alcohol inhibits fetal glucose uptake and growth.
        J Neuroteratol Toxicol. 1989; 11: 215-219
        • Pullen GL
        • Singh SP
        • Snyder AK
        Growth patterns of the offspring of alcohol-fed rats.
        Growth Dev Aging. 1988; 52: 85-89
        • D'Ercole AJ
        • Underwood LE
        Estimation of tissue concentrations of somatomedin Math Eq.
        in: 3rd ed. Methods Enzymol. 146. 1987: 227-233
        • Zapf J
        • Walter H
        • Froesch ER
        Radioimmunological determination of insulin-like growth factors I and II in normal subjects and in patients with growth disorders and extrapancreatic tumor hypoglycemia.
        J Clin Invest. 1981; 68: 1321-1330
        • Romanus JA
        • Yang YWH
        • Adams SO
        • et al.
        Synthesis of insulin-like growth factor II in fetal tissues: translation of IGF-II ribonucleic acid and processing of pre-pro-IGF-II.
        Endocrinology. 1988; 122: 709-716
        • Furlanetto RW
        • Underwood LE
        • Van Wyk JJ
        • D'Ercole AJ
        Estimation of somatomedin-C levels in normals and patients with pituitary disease by radioimmunoassay.
        J Clin Invest. 1977; 60: 648-657
        • Tanaka H
        • Ashami O
        • Hayano T
        • Sasaki I
        • Yoshitake Y
        • Nishikawa K
        Identification of a family of insulin-like growth factor II secreted by cultured rat epithelial like cell line 18,54-SF: application of a monoclonal antibody.
        Endocrinology. 1989; 124: 870-877
        • Chomcyznski P
        • Sacchi N
        Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction.
        Anal Biochem. 1987; 162: 156-159
        • Rosen KM
        • Villa-Komaroff
        An alternate method for the visualization of RNA in formaldehyde agarose gels.
        Focus (BRL Publication). 1990; 12: 23-24
        • Whitfield HJ
        • Bruni CB
        • Funzio R
        • Terrel JE
        • Nissley SP
        • Rechler MM
        Isolation of a cDNA clone encoding rat insulin-like growth factor-II precursor.
        Nature. 1984; 312: 277-280
        • Casella SJ
        • Smith EP
        • Van Wyk JJ
        • et al.
        Isolation of rat testis cDNAs encoding an insulin-like growth factor-I precursor.
        DNA. 1987; 6: 325-330
      1. Ausbel FM Brent R Kingston RE Current protocols in molecular biology. Green-Wiley Interscience Publications, New York1987: 4.9.7 (suppl 23)
        • Hossenlopp P
        • Seurin D
        • Segovia-Quinson S
        • Hardouin S
        • Binoux M
        Analysis of serum insulin-like growth factor binding proteins using western blotting: use of the method for titration of the binding proteins and competitive binding studies.
        Anal Biochem. 1986; 154: 138-143
        • Davenport ML
        • D'Ercole AJ
        • Underwood LE
        Effect of maternal fasting on fetal growth, serum insulin-like growth factors, and tissue IGF messenger ribonucleic acids.
        Endocrinology. 1990; 126: 2062-2067
        • Hoyt EC
        • Van Wyk JJ
        • Lund PK
        Tissue and development specific regulation of a complex family of rat insulin-like growth factor I messenger ribonucleic acids.
        Mol Endocrinol. 1988; 2: 1077-1086
        • Romanus JA
        • Terrel JE
        • Yang YWH
        • Nissley SP
        • Rechler MM
        Insulin-like growth factor carrier proteins in neonatal and adult rat serum are immunologically different: demonstration using a new radioimmunassay for the carrier protein from BRL-3A rat liver cells.
        Endocrinology. 1986; 118: 1743-1758
        • Halmesmaki E
        • Valimaki M
        • Karonen SL
        • Ylikorkala O
        Low somatomedin C and high growth hormone levels in newborns damaged by maternal alcohol abuse.
        Obstet Gynecol. 1989; 74: 366-370
        • Bondy CCA
        • Werner H
        • Roberts CTJ
        • LeRoith D
        Cellular pattern of insulin-like growth factor I (IGI) and type I IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression.
        Mol Endocrinol. 1990; 4: 1386-1388
        • Adashi EY
        • Resnick CE
        • Rosenfeld RG
        Insulin-like growth factor-I (IGF-I) and IGF-II hormonal action in cultured rat granulosa cells: mediation via type I but not type II IGF receptors.
        Endocrinology. 1990; 126: 216-222
        • Osborne CK
        • Coronado EB
        • Kitten LJ
        • et al.
        Insulin-like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor.
        Mol Endocrinol. 1989; 3: 1701-1709
        • Jones PJH
        • Leichter J
        • Lee M
        Placental blood flow in rats fed alcohol before and during gestation.
        Life Sci. 1981; 29: 1153-1159
        • Sonntag WE
        • Boyd RL
        Diminished insulin-like growth factor-1 levels after chronic ethanol: relationship to pulsatile growth hormone release.
        Alcohol Clin Exp Res. 1989; 13: 3-7
        • Tewari S
        • Greenberg SA
        • Do K
        • Grey PA
        The response of rat brain protein synthesis to ethanol and sodium barbital.
        Alcohol Drug Res. 1987; 7: 243-258
        • Unterman TG
        • Simmons RA
        • Glick RP
        • Ogata ES
        Circulating levels of insulin, insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins in the small for gestational age fetal rat.
        Endocrinology. 1993; 132: 327-336
        • Unterman TG
        • Oehler DT
        • Gotway MB
        • Morris PW
        Production of the rat type 1 insulin-like growth factor-binding protein by well differentiated H4EIIC3 hepatoma cells: identification, purification, and N-terminal amino acid analysis.
        Endocrinology. 1990; 127: 789-797
        • Suikkari AM
        • Koivisto VA
        • Koistinen R
        • Seppala M
        • Yki-Jarvinen H
        Dose-response characteristics for suppression of low molecular weight plasma insulin-like growth factor-binding protein by insulin.
        J Clin Endocrinol Metab. 1989; 68: 135-140
        • Singh SP
        • Snyder AK
        Ethanol ingestion during pregnancy: effects on pregnant rats and their offspring.
        J Nutr. 1982; 112: 98-103
        • Freinkel N
        Banting lecture 1980. Of pregnancy and progeny.
        Diabetes. 1980; 29: 1023-1035