Gene-environment Interactions Underlying the Developmental Origins of Health and Disease

• Main Author: Knight, Brian Spencer
• Other Authors: Lye, Stephen J.
• Language: en_ca
• Published: 2008
• Subjects: physiology; 0719
• Online Access: http://hdl.handle.net/1807/24220

Retrospective epidemiological studies of British cohorts have found an inverse relationship between birth size and rates of mortality from cardiovascular disease and stroke. Subsequently, further studies in humans and in animals have demonstrated that there is an inverse relationship with a combination of suboptimal prenatal and postnatal environments and the development of the metabolic syndrome (insulin resistance, hypertension, obesity and dyslipidemia). However, recently it has been reported that not all individuals exposed to these environments develop these conditions, suggesting that an individual’s genotype may contribute to the eventual outcome. Phylogenetically distinct, murine strains allow the genetic dissection of complex phenotypic traits; however, to date, they have not been utilized to evaluate the gene-environment interaction underlying these inverse relationships. Thus, A/J and C57BL/6J mice were subjected to prenatal undernutrition, to model an adverse intra-uterine environment, and although prenatal undernutrition resulted in fetal growth restriction of equal magnitude, remarkable strain differences were observed. At the end of gestation C57BL/6J mice showed significant alterations in fetal organ weights (liver, kidneys and placenta) and glucocorticoids (elevation). Postnatally, C57BL/6J offspring demonstrated catch-up growth, obesity, impaired glucose tolerance, insulin resistance, increased blood pressure, liver dysfunction and altered cardiovascular function compared to strain and gender matched controls. The A/J strain was resistant to the development of prenatal and postnatal pathologies, except they also demonstrated alterations in cardiovascular function. Females of both strains displayed a more moderate phenotype than the males. Although feeding undernutrition mice an atherogenic diet postnatally did not exacerbate the phenotype, postnatal dietary supplementation of omega-3 long chain unsaturated fatty acids completely reversed the undernutrition induced altered metabolic phenotype in C57BL/6J. Microarray analysis revealed that adult A/J and C57BL/6J mice have distinct gene expression profiles, under control dietary conditions, and that this differential strain expression profile changes in adult offspring in response to prenatal undernutrition. The expression profiles predicted onset of metabolic and liver diseases within the C57BL/6J strain, clearly linking the observed phenotype to alterations in gene expression. These expression differences were also linked to inherent strain differences in the genetic code where a disproportionate number of differential expressed genes had function altering polymorphisms.