Effect of alpha-fetoprotein and derived peptides on insulin- and estrogen-induced fetotoxicity.
Both insulin and estrogen are well recognized as growth-promoting substances at physiological concentrations, but they function as teratogens at high doses. Both agents can affect alterations in fetal and maternal serum human alpha-fetoprotein (HAFP) levels during pregnancy. In the present study, we have employed animal models of both insulin and estrogen fetotoxicity and teratogenicity in order to study the growth-regulatory properties of HAFP and its derived peptides (HAFP/PEP). We report here the effects of HAFP/PEP on fetotoxicity, congenital malformations, and growth retardation in developing chick and murine fetuses. In the insulin model, HAFP/PEP were effective in reducing both fetal mortality and anatomic anomalies, with the result that growth-retarded fetuses were produced. With HAFP/PEP treatment, fetal demise was reduced by as much as 73 and 63% in murine and chick fetuses, respectively, while fetal anomalies were diminished by 50% during chick development. Genebank searches of identity/similarity in a HAFP/PEP fragment identified matches with a number of proteins associated with glucose, pH, ionic, osmotic, and oxidative stresses, and with heat shock, in addition to stress proteins related to protein folding/unfolding processes. It was proposed that the peptide segment on HAFP may represent a topographic 'hotspot', sensitive to stress/shock conditions, which exhibits a propensity for conformational alteration in the tertiary structure of the fetal protein.
Butterstein
George
G
Department of Biological Sciences, Union College, Schenectady, NY 12308, USA.
Morrison
Jennifer
J
Mizejewski
G J
GJ
D000418:Albumins / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002642:Chick Embryo; D002645:Chickens; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D006360:Heat-Shock Proteins / Q000235:genetics; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007328:Insulin / Q000633:toxicity*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D011247:Pregnancy; D013723:Teratogens / Q000633:toxicity*; D000509:alpha-Fetoproteins / Q000235:genetics / Q000494:pharmacology*
D000418:Albumins; D004967:Estrogens; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D013723:Teratogens; D000509:alpha-Fetoproteins