title: Bone-specific gene expression patterns and whole bone tissue of female mice are programmed by early life exposure to soy isoflavones and folic acid.
abstract: Female mice exposed to soy isoflavones (ISO) during early postnatal life have improved bone outcomes at adulthood. Since long-lasting effects may be mediated by DNA methylation, we hypothesized that providing supplemental folic acid (FA), a methyl donor, during early life, would enhance the positive effect of ISO to bone health. Bone-specific gene expression patterns were studied to understand potential mechanisms. CD-1 dams (n=36) were randomized to adequate or supplemental levels of FA (2 or 8 mg/kg diet) during pregnancy and lactation, and offspring received corn oil or ISO (7 mg/kg body weight/d) from postnatal day 1 to 10. From weaning, pups were fed an adequate FA diet and were studied to 4 months of age. Female offspring exposed to supplemental FA+ISO had higher bone mineral density (BMD), trabecular connectivity and peak load at the lumbar spine compared to females exposed to adequate FA. Female offspring exposed to adequate FA+ISO or supplemental FA had higher (P<.05) BMD and greater resistance to fracture at the lumbar spine and the femur; higher trabecular connectivity at the lumbar spine; and lower expression of DNA methyltransferase 3a (Dnmt3a) and neuropeptide Y (NPY) in the femur compared to mice exposed to adequate FA. In addition, only mice exposed to adequate FA+ISO had microstructural improvements at the femur neck and higher serum osteoprotegrin (OPG) and insulin growth factor-I (IGF-I). In summary, exposure to supplemental FA did not enhance the positive effect of ISO in bone. However, exposure to adequate FA+ISO or supplemental FA improved bone at least in part by suppressing Dnmt3a and NPY.
authors.affiliation: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 3E2; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, 02115.
authors.forename: Jovana
authors.initials: J
authors.lastname: Kaludjerovic
authors.affiliation: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 3E2; Center for Bone and Muscle Health, Faculty of Applied Health Sciences, Brock University, St. Catharines, Ontario, Canada, L2S 3A1. Electronic address: wward@brocku.ca.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Ward
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000032:analysis; D000090205:DNA Methyltransferase 3A; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D015870:Gene Expression; D007529:Isoflavones / Q000008:administration & dosage*; D007774:Lactation; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D009478:Neuropeptide Y / Q000032:analysis; D011247:Pregnancy; D013025:Glycine max / Q000737:chemistry*
chemical_list: C000715535:Dnmt3a protein, mouse; D007529:Isoflavones; D009478:Neuropeptide Y; D005492:Folic Acid; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: Bone development; DNA methyltransferase; Female CD-1 mice; Folic acid; Neuropeptide Y; Soy isoflavones