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United States Department of Agriculture

Agricultural Research Service

Research Project: IMPACT OF EARLY DIETARY FACTORS ON CHILD DEVELOPMENT AND HEALTH

Location: Arkansas Children's Nutrition Center

Title: Epigenetic control of fetal bone development through HoxA10 in the rat

Authors
item Chen, Jinran -
item Zhang, Jian -
item Lazarenko, Oxana -
item Wynne, Rebecca -
item Blackburn, Michael -
item Ronis, Martin -
item Shankar, Kartik -
item Badger, Thomas

Submitted to: American Society for Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: April 12, 2011
Publication Date: October 1, 2011
Citation: Chen, J., Zhang, J., Lazarenko, O.P., Wynne, R.A., Blackburn, M.L., Ronis, M.J., Shankar, K., Badger, T.M. 2011. Epigenetic control of fetal bone development through HoxA10 in the rat. Journal of Bone and Mineral Research. 26(Suppl 1):#MO0262.

Interpretive Summary: It has been known that quality of nutrition during early life impact the risk of low bone mass and fracture later in life. Maternal consumption of high-fat diets has been demonstrated to affect health outcomes, such as: brain development; obesity; insulin resistance; and hypertension. Here, we show that cells from obese rat moms fed a high fat diet (HFD) have significantly less potential to develop into mature bone forming cells (osteoblasts) compared to cells from AIN-93G diet-fed controls. Cells taken from fetuses from obese rat moms express lower levels of bone formation markers (alkaline phophatase, ALP), but higher levels of adipose tissue formation marker (PPAR gamma) compared to fetal cells from control moms fed low fat diets (p<0.05). Particularly a gene call genes homeodomain-containing factor A10 (HoxA10) in these fetal cells from HFD offspring was down-regulated. These results suggest that maternal obesity may affect fetal skeletal development through down regulation of the HoxA10 gene by altered free fatty acid composition in the maternal circulation, which may lead to an increase of the prevalence of low bone mass in their offspring later in life.

Technical Abstract: Epidemiological studies show that quality of nutrition during intrauterine and early postnatal life impact the risk of low bone mass and fracture later in life. Maternal consumption of high-fat diets has been demonstrated to affect health outcomes, such as: brain development; obesity; insulin resistance; and hypertension. Here, we show that fetal rat osteogenic calvarial cells (FOCC) from obese rat dams fed a high fat diet (HFD) have significantly less potential to develop into mature osteoblasts compared to cells from AIN-93G diet-fed controls. These FOCCs taken from E18.5 embryos from obese rat dams express lower levels of alkaline phophatase (ALP), but higher levels of PPAR' compared to fetal cells from control dams fed low fat diets (p<0.05). Profiling of transcriptional genes for osteogenesis revealed a 15-fold decrease in the homeodomain-containing factor A10 (HoxA10) in these FOCCs from HFD offspring. Significant methylation of the HoxA10 promoter was found in these FOCCs, as well as in ST2 cells treated with a mixture of free fatty acids (palmitic, stearic, oleic, linoleic and arachidonic acid in the ratio of 5:1:2:3:1 similar to that found in rat serum from HFD rats), this was accompanied by lower expression of alkaline phophatase (ALP), but higher levels of PPAR'. Silencing of the HoxA10 gene ex vivo in control FOCCs produced effects similar to those observed in FOCCs from HFD offspring. Treatment of FOCCs from control rats and ST2 cells with an artificial mixture of free fatty acid, significantly down regulated the HoxA10 protein expression and cells exhibit triglyceride accumulation as measured by Oil Red O staining. These results suggest that maternal obesity may affect fetal skeletal development through down regulation of the HoxA10 gene by altered free fatty acid composition in the maternal circulation, which may lead to an increase of the prevalence of low bone mass in their offspring later in life.

Last Modified: 9/2/2014
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