Effect of α-Fetoprotein and Derived Peptides on Insulin- and Estrogen-Induced Fetotoxicity

Abstract

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 α-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.

Transformed Alpha-Fetoprotein (t-AFP) Levels in Women with Threatened Preterm Labor

“…The t-AFP molecule seems to play a role in fetal stress conditions, as previously shown in cases of animal insulin-and estrogen-induced fetotoxicity [22] and in the higher MSt-AFP levels found in human growth-retarded fetuses [24] . Our results seems to indicate that the existence of uterine contractions before term in the TPL group does not suppose any stress condition for the fetus as its levels decrease in this situation.…”

“…In this conformational variant of AFP (transformed AFP or t-AFP), a certain peptidic region, which is hidden inside the third domain of the native folded protein, is exposed. When this occurs, the molecule shows antitumoral and antigrowth properties [18][19][20][21][22] .…”

Update of Alpha Fetoprotein Growth-Inhibitory Peptides as Biotherapeutic Agents for Tumor Growth and Metastasis

“…Previous studies have also shown that the growth-inhibitory property of P149 appears to cross species barriers and is observed in amphibians, birds, and mammals including man and rodents ( table 1 ). These observations suggest an inhibitory mechanism of action of P149 that is common to many different kinds of animal cells [26,27] . The shared events of GIP's action appear to occur primarily as cell surface activities being representative of cell migration, aggregation, agglutination, cytoskeletal-mediated shape changes, and endocytosis [12] .…”

Maternal Serum Transformed α-Fetoprotein Levels in Women with Intrauterine Growth Retardation

“…One major function of this peptide seems to be suppression of growth in neonatal and tumor cells. This function prompted the name of 'growth-inhibitory peptide' [3,4] . Treatments with this peptide in animals have been reported to be effective in reducing both fetal demise and anatomic anomalies but at the expense of an increased rate of growth retarded fetuses, and it was speculated that this peptide may have a role in the pathogenesis of some cases of fetal growth retardation and/or be used as a marker in these cases [3] .…”