Date of Award

Winter 12-15-2014

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Increasing maternal age is widely acknowledged to lead to greater likelihood of pregnancy complications and congenital abnormalities, but the basis of this effect has not been well studied. Often dismissed as the product of oocyte ageing, the mechanistic basis of this maternal age effect is likely more complex.

Congenital heart disease is a classic complex disease with multiple genetic and environmental modifiers, including maternal age. Maternal ageing is a known risk-factor in humans, and has been shown to exist in an Nkx2-5 haploinsufficient mouse model for the disease. This mouse model's maternal age risk is dependent upon strain background, with C57BL/6N pure line and FVB/N x C57BL/6N F2 intercross pups being at risk due to maternal ageing, and A/J x C57BL/6N F2 intercrosses showing no maternal age risk. This indicates a maternal genetic component to maternal age risk, and implies that though ageing is inevitable, the negative effects on offspring are not. Using this model, this study examines whether the maternal age effect is due to oocyte ageing or a maternally intrinsic factor, shows a remediating treatment for maternal age risk, and defines epigenetic changes in offspring resulting from maternal ageing.

Reciprocal ovarian transplants between old and young FVB/N x C57BL/6N F1 mothers were used to localize the basis of the maternal age effect to the mother. In spite of ovulating from ovaries aged well beyond the mouse's normal reproductive life span, young mothers were at no higher risk for ventricular septal defects (VSD), while old mothers showed a persistent high risk for VSD in spite of ovulating young oocytes.

Voluntary exercise experiments where FVB/N x C57BL/6N F1 mothers were given access to running wheels over the course of their lifetime showed that exercise decreased maternal age risk to levels indistinguishable from that of young mothers. Additionally, late-onset exercise was shown to be effective at reducing maternal age risk after just three months' exposure, even with no overt changes in body mass, composition, or glucose tolerance.

To study the impact of maternal ageing on epigenetic profiles, reduced representation bisulfite sequencing was used to compare aged and young sedentary fetal hearts and aged exercise fetal heart tissue. These comparisons showed eight differentially methylated regions, altered by maternal ageing but recovered by exercise treatment.

These studies are conclusive proof that nonsyndromic maternal age risk is not due to oocyte ageing, but instead to a modifiable, maternally intrinsic risk factor. These studies also suggest the possibility of exercise as a prescription to prevent or turn back maternal age's negative impacts. Exercise as an intervention poses tempting possibilities as a safe intervention for at-risk populations. Further investigation into the mechanistic influence of epigenetics in this effect may identify risk biomarkers for testing in maternal populations, and may provide keys to the underlying genetic architecture for congenital malformations such as congenital heart disease.


English (en)

Chair and Committee

Patrick Y Jay

Committee Members

Sessions F Cole, Donald F Conrad, Kelle H Moley, David B Wilson


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