Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction

PLoS One. 2017 Apr 6;12(4):e0175467. doi: 10.1371/journal.pone.0175467. eCollection 2017.

Abstract

Growth deficits are common in cystic fibrosis (CF), but their cause is complex, with contributions from exocrine pancreatic insufficiency, pulmonary complications, gastrointestinal obstructions, and endocrine abnormalities. The CF mouse model displays similar growth impairment despite exocrine pancreatic function and in the absence of chronic pulmonary infection. The high incidence of intestinal obstruction in the CF mouse has been suggested to significantly contribute to the observed growth deficits. Previous studies by our group have shown that restoration of the cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium prevents intestinal obstruction but does not improve growth. In this study, we further investigate growth deficits in CF and gut-corrected CF mice by assessing insulin-like growth factor 1 (IGF-1). IGF-1 levels were significantly decreased in CF and gut-corrected CF adult mice compared to wildtype littermates and were highly correlated with weight. Interestingly, perinatal IGF-1 levels were not significantly different between CF and wildtype littermates, even though growth deficits in CF mice could be detected late in gestation. Since CFTR has been suggested to play a role in water and nutrient exchange in the placenta through its interaction with aquaporins, we analyzed placental aquaporin expression in late-gestation CF and control littermates. While significant differences were observed in Aquaporin 9 expression in CF placentas in late gestation, there was no evidence of placental fluid exchange differences between CF and control littermates. The results from this study indicate that decreased IGF-1 levels are highly correlated with growth in CF mice, independent of CF intestinal obstruction. However, the perinatal growth deficits that are observed in CF mice are not due to decreased IGF-1 levels or differences in placenta-mediated fluid exchange. Further investigation is necessary to understand the etiology of early growth deficits in CF, as growth has been shown to be a significant factor in disease outcomes.

MeSH terms

  • Animals
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / physiopathology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Female
  • Growth*
  • Insulin-Like Growth Factor I / genetics*
  • Intestinal Obstruction / complications
  • Mice
  • Mice, Transgenic
  • Placenta / metabolism
  • Pregnancy

Substances

  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Insulin-Like Growth Factor I

Grant support

This work was supported by grants from the Cystic Fibrosis Foundation (Hodges11G0, https://www.cff.org/CFF) and the National Institutes of Health (P30DK27651 and R24RR032425, https://www.nig.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.