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Elevated Circulating Insulin-Like Growth Factor Binding Protein-1 Is Sufficient to Cause Fetal Growth Restriction

Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development (C.S.W., V.K.M.H.), Departments of Pediatrics, Obstetrics and Gynecology and Biochemistry, University of Western Ontario, Children’s Health Research Institute, London, Ontario, Canada, N6C 2V5; London Regional Cancer Program (P.B., S.-P.Y.), University of Western Ontario, London, Ontario, Canada, N6A 4L6; Division of Pediatric Endocrinology (M.A.), David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095; and Diagnostic Systems Laboratories (Canada) Inc. (J.K.), Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto and Mount Sinai Hospital, Toronto, Ontario, Canada, M5G 1X5

Address all correspondence and requests for reprints to: Dr. Carole S. Watson, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5. E-mail: watson{at}mshri.on.ca.

IGF binding protein-1 (IGFBP-1) inhibits the mitogenic actions of the IGFs. Circulating IGFBP-1 is elevated in newborns and experimental animals with fetal growth restriction (FGR). To establish a causal relationship between high circulating IGFBP-1 and FGR, we have generated transgenic mice using the mouse -fetoprotein gene promoter to target overexpression of human IGFBP-1 (hIGFBP-1) in the fetal liver. These transgenic mice (AFP-BP1) expressed hIGFBP-1 mainly in the fetal hepatocytes, starting at embryonic d 14.5 (E14.5), with lower levels in the gut. The expression peaked at 1 wk postnatally (plasma concentration, 474 ± 34 ng/ml). At birth, AFP-BP1 pups were 18% smaller [weighed 1.34 ± 0.02 g compared with 1.62 ± 0.04 g for wild type (WT); P < 0.05], and they did not demonstrate any postnatal catch-up growth. The placentas of the AFP-BP1 mice were larger than WT from E16.5 onwards (150 ± 12 for AFP-BP1 vs. 100 ± 5 mg for WT at E16.5; P < 0.05). Thus, this model of FGR is associated with a larger placenta, but without postnatal catch-up growth. Overall, these data clearly demonstrate that high concentrations of circulating IGFBP-1 are sufficient to cause FGR.

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