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Submitted on May 18, 2005
Accepted on November 9, 2005
CIHR Group in Fetal and Neonatal Health and Development, Departments of Pediatrics, Obstetrics & Gynecology, and Biochemistry, University of Western Ontario, Children's Health Research Institute, London, ON, N6C 2V5; London Regional Cancer Program, University of Western Ontario, London, ON, Division of Pediatric Endocrinology, David Geffen School of Medicine at the UCLA, Los Angeles, CA, Diagnostic Systems Laboratories (Canada) Inc, Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto and Mount Sinai Hospital, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: watson{at}mshri.on.ca.
Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits the mitogenic actions of the insulin-like growth factors. 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 E14.5, with lower levels in the gut. The expression peaked at 1 week 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 WT; P < 0.05) and they did not demonstrate any postnatal catch-up growth. The placentae of the AFP-BP1 mice were larger than WT from E16.5 onwards (AFP-BP1: 150 ± 12 vs. WT: 100 ± 5 mg 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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