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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Placental-mediated fluid exchange is not different between CF and control fetuses.(A) Fetal body and placental water weight at e18 was not significantly different between CF and control fetuses. (B) Equilibration of 2H2O between dam and CF and control fetuses at e18 were not significantly different. (n≥10; data represent mean±SEM).
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pone.0175467.g005: Placental-mediated fluid exchange is not different between CF and control fetuses.(A) Fetal body and placental water weight at e18 was not significantly different between CF and control fetuses. (B) Equilibration of 2H2O between dam and CF and control fetuses at e18 were not significantly different. (n≥10; data represent mean±SEM).

Mentions: Given the importance of aquaporins in placental-mediated water exchange for the fetus, we hypothesized that the altered Aqp9 expression may lead to decreased fluid uptake, leading to the observed weight difference between CF and control fetuses and newborn pups. We calculated fetal fluid transfer using two independent measures: percent water weight and by the isotopic dilution method using deuterium-labeled water (as described in Methods). There were no significant differences between water weight in the body or placenta between the CF and control e18 fetuses (Fig 5A), and there were no detectable differences in fluid exchange between the dam and CF and control littermates (Fig 5B). Therefore, the differences in neonatal birth weight between the CF and control mice are not due to differences in placental water transfer. However, further studies are needed to interpret the increase in Aqp9 expression in CF placentas given this absence in difference in placental water transfer between CF and control fetuses. For example, it is possible that the increase in Aqp9 expression does not coincide with an increase in protein levels or, alternatively, increased Aqp9 expression may lead to increased protein levels with no difference in Aqp9 function. Interestingly, a previous study noted that mothers fed a hypercaloric diet gave birth to CF babies of higher birth weight as compared with mothers on a normal diet, suggesting the possibility of placental nutrient exchange differences in CF still needs to be determined [52].


Growth deficits in cystic fibrosis mice begin in utero prior to IGF-1 reduction
Placental-mediated fluid exchange is not different between CF and control fetuses.(A) Fetal body and placental water weight at e18 was not significantly different between CF and control fetuses. (B) Equilibration of 2H2O between dam and CF and control fetuses at e18 were not significantly different. (n≥10; data represent mean±SEM).
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5383306&req=5

pone.0175467.g005: Placental-mediated fluid exchange is not different between CF and control fetuses.(A) Fetal body and placental water weight at e18 was not significantly different between CF and control fetuses. (B) Equilibration of 2H2O between dam and CF and control fetuses at e18 were not significantly different. (n≥10; data represent mean±SEM).
Mentions: Given the importance of aquaporins in placental-mediated water exchange for the fetus, we hypothesized that the altered Aqp9 expression may lead to decreased fluid uptake, leading to the observed weight difference between CF and control fetuses and newborn pups. We calculated fetal fluid transfer using two independent measures: percent water weight and by the isotopic dilution method using deuterium-labeled water (as described in Methods). There were no significant differences between water weight in the body or placenta between the CF and control e18 fetuses (Fig 5A), and there were no detectable differences in fluid exchange between the dam and CF and control littermates (Fig 5B). Therefore, the differences in neonatal birth weight between the CF and control mice are not due to differences in placental water transfer. However, further studies are needed to interpret the increase in Aqp9 expression in CF placentas given this absence in difference in placental water transfer between CF and control fetuses. For example, it is possible that the increase in Aqp9 expression does not coincide with an increase in protein levels or, alternatively, increased Aqp9 expression may lead to increased protein levels with no difference in Aqp9 function. Interestingly, a previous study noted that mothers fed a hypercaloric diet gave birth to CF babies of higher birth weight as compared with mothers on a normal diet, suggesting the possibility of placental nutrient exchange differences in CF still needs to be determined [52].

View Article: PubMed Central - PubMed

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.

No MeSH data available.