Our laboratory has previously used immunological methods to demonstrate four distinct proteins which become detectable in the plasma of pregnant women, but are not found in non-pregnant women or in males. The proposed research is aimed at clarifying the biochemical identity and biological role of each of these pregnancy-associated plasma proteins (PAPP's), as well as determining the potential pathological significance of excessive or insufficient levels of any of these proteins in diseases of pregnancy. Extensive tests and direct immunological comparisons with reagents from other laboratories revealed that two of them (PAPP-A and PAPP-B) are newly discovered proteins and as of now have not yet been studied by other investigators. PAPP-C is being investigated by several laboratories. All four PAPP's are pregnancy specific and distinct from the pregnancy zone protein (PZP). We have studied the physico-chemical properties of each of the PAPP's, such as molecular weights (1,000,000, -B; 750,000, -A; 110,000, -C; and 20,000, -D (HPL)); isoelectric point; sedimentation rate; heat and pH stability; and electrophoretic mobility. Each of them has been purified at least 100 fold from late pregnancy plasma. Monospecific antisera to them have been prepared. All the PAPP's are synthesized by the placental trophoblast. Their concentration in maternal plasma increases steadily as gestation progresses, and drops rapidly postpartum. Some normal obstetric parameters (e.g., parity, placental weight) were correlated with some of them. Preliminary studies further revealed that pregnancies with twin, diabetes, and toxemia may be associated with abnormal levels of some of these proteins. Analogous cross-reacting proteins were found in old world monkeys and chimpanzees, but not in rats, mice, and new world monkeys. Cross-reacting PZP was found in all the primates tested, but it was detected strongly in non-pregnant as well as pregnant monkeys. In fact, PZP appears to decrease in concentration during gestation in old world monkeys.