PARENT SESSION

(58) FETAL PROGRAMMING: ALTERED INSULIN-LIKE GROWTH FACTOR SIGNALING UNDERLIES INTRAUTERINE GROWTH RETARDATION AND POST-NATAL CATCH-UP GROWTH IN FEMALE SHEEP EXPOSED IN UTERO TO TESTOSTERONE EXCESS.

Crespi, Erica ¹, Seckler, Teresa¹, Manikkam, Mohan¹, Padmanabhan, Vasantha¹, ¹ University of Michigan, Ann Arbor, MI

ABSTRACT- Previously we found that experimentally elevated maternal testosterone (T) during 60-90 days of gestation resulted in intrauterine growth retardation (IUGR) and an increased growth rate (catch-up growth) between 2-4 months of age in female lambs. This study tested the hypothesis that changes in insulin-like growth factor (IGF) signaling are associated with IUGR and catch-up growth of prenatal T females. Developmental changes in plasma IGF-1 and IGF binding proteins (IGFBPs) of control (C) and prenatal T females were determined on fetal day (d) 65, 90, 140 (n=6-7/treatment/time) and at 4 months of age (n=14-16/treatment), the time when catch-up growth occurs. Total IGF-1 was measured by radioimmunoassay and IGFBPs by Western ligand blot. All values were adjusted for body mass in the statistical analyses; here we report the mean ± SEM. Plasma IGFBP-1, an inhibitor of IGF bioactivity, was elevated by 27% in prenatal T-treated fetuses at 65d (P=0.04), although there were no differences in plasma IGF-1 or body mass at this time. By 90d, plasma concentrations of IGF-1 (C: 72.7 ± 5.7, T: 92.9 ± 3.3 ng/mL; P=0.02) and IGFBP-3 (C: 1238 ± 41, T: 1420 ± 49 densitometric units, P=0.01), a promoter of IGF bioactivity, were elevated in prenatal T-treated fetuses. This compensation by the fetal IGF axis was transient, as both IGF-I and IGFBP-3 were reduced by 140d when prenatal T-treated female fetuses first showed IUGR relative to C females (body mass C:4.9 ± 0.15, T:3.7 ± 0.23 kg; P < 0.05). By 4 months after birth, T-treated females exhibited catch-up growth (ANOVA time × treatment effect; P < 0.01) and elevations in plasma IGF-1 (C: 169.6 ± 11.4, T: 204.6 ± 12.8 ng/mL; P=0.02) and IGFBP-3 (P=0.04) compared with C females. Our data support the premise that 1) exposure to elevated T during the 2nd trimester alters the developmental trajectory of the IGF axis and 2) changes in IGF bioavailability as dictated by changes in IGF-1 and/or IGFBP levels may underlie the IUGR and peripubertal catch-up growth observed in prenatal T-treated females. Although the mechanism linking excess prenatal T with alterations in IGF axis activity is unknown, our findings are consistent with the hypothesis that T-induced depression of IGF signaling early in fetal development may have significant effects on life-long growth. Supported by NIH HD 41098 & P01 HD 44232.

KEY WORDS: fetal programming, testosterone, intrauterine growth retardation, insulin-like growth factor