Title:

Programming of Bone and Reproductive Health by Early Life Exposure to Soy Isoflavones and Folic Acid in CD-1 Mice

Advisor: Ward, Wendy
Issue Date: Jun-2013
Abstract (summary): Previous studies showed that exposure to soy isoflavones (ISO) during the first 5 days of life improves bone mineral density (BMD), structure and strength of the lumbar spine in CD-1 female mice at adulthood. In continuing this research, a first step was to optimize the CD-1 mouse model. As such, the first two studies confirmed that once-daily subcutaneous exposure to ISO results in total serum ISO levels that mimic those of infants fed soy protein formula, and that exposure for the first 10 rather than 5 days of life is needed to improve bone outcomes in vertebra as well as femurs. I hypothesized that early life exposure to ISO was improving adult bone outcomes by altering expression of genes that modulate bone development, possibly via DNA methylation, and that providing a methyl donor such as folic acid (FA) to the maternal diet during pregnancy and lactation could enhance the positive effects of ISO. Female and male CD-1 mice exposed to an adequate level of FA and ISO had higher BMD, improved trabecular connectivity and greater resistance to fracture compared to mice not exposed to ISO. In contrast, exposure to supplemental levels of FA in combination with ISO did not result in improved bone outcomes. Exposure to adequate levels of FA and ISO lowered neuropeptide Y (NPY) gene expression by 5.7-fold, while exposure to supplemental levels of FA and ISO up-regulated the expression of beta-catenin (Ctnnb1) and parathyroid hormone receptor (PTHr1) gene by 1.6- and 1.7-fold, respectively, than mice exposed to adequate FA without ISO. NPY is a neurotransmitter which when suppressed in osteoblasts promotes bone formation while Ctnnb1 and PTHr1 are modulators of bone resorption. Thus, by inducing long-term changes in gene expression, FA and ISO may improve bone development. In contrast, reproductive health was adversely affected and identified the first 5 and 10 days of life as a sensitive window of development during which exposure to ISO can alter structural development of ovaries and uterus. In conclusion, early life exposure to ISO and FA can favourably modulate bone development but other hormone-sensitive tissues are adversely affected in this model.
Content Type: Thesis

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https://hdl.handle.net/1807/68948

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