Insulin-like growth factor (IGF) peptides are critical for fetal growth and development. In humans and other animals, circulating concentrations of IGF-I, IGF-II, and the major circulating binding protein, IGFBP-3, are correlated with birthweight. This study was undertaken to examine possible correlations between fetal weight and components of the IGF system in the rabbit, a polytoccus species that normally has a wide variation in fetal weight within a single litter. At term (30 days), weights of fetuses (n=48) ranged from 38-65 g, with a 1.5-2 fold range within each doe (n=5). Fetal serum concentrations(RIA) of IGF-I ranged from 29-67 ng/ml and of IGF-II ranged from 815-2157 ng/ml, with no significant correlation with fetal weight, even within a single litter. Western ligand blot (WLB) analysis of fetal serum demonstrated a faint 45-40 kDa IGFBP-3 band, as well as, predominant 29 and 24 kDa bands. Densitometric analysis showed no correlation between the 45-40 kDa doublet and fetal size, while an inverse correlation was found for the predominant 29 kDa IGFBP, r=0.43, p<0.05. Neutral size exclusion chromatography and WLB analysis of the fractionated serum revealed the 45-40 kDa IGFBP within the 150kDa region while the smaller IGFBPs eluted in the 44kDa region of the chromatograph. Thus, IGFBP-3 circulates in the 150 kDa ternary complex in rabbit fetuses, unlike in human fetuses. IGFBP-3 mRNA was primarily expressed in the placenta as demonstrated by Northern analysis of liver, kidney and placenta. The level of placental mRNA expression was independent of fetal size. Thus, in contrast to more widely studied monotoccus species such as humans and sheep, there was no correlation between IGF-I, IGF-II, or IGFBP-3, but there was an inverse correlation between a 29 kDa IGFBP, and fetal weight at term in rabbits. These data suggest that different parts of the fetal IGF system are under independent regulatory controls. Because fetal size in rabbits is determined predominately by nonrandom position within the uterine horn, a local uteroplacental factor, such as relative blood flow, may be an important regulator of fetal IGF activity.Funded by NIH HL44941 and HD28703. Dr. Labarta was supported by Fondo del Investigation Sanitaria (94/5373), Spain.