Transgenerational Developmental Programming of Ovarian Reserve

Abstract

Exposure to an adverse early-life environment leads to long-term health problems, many of which are recapitulated in subsequent generations. The female reproductive tract is particularly sensitive to early-life influences, and plays a pivotal role in programming the conceptus. We examine the influence of suboptimal grandmaternal diet on reproductive potential of granddaughters in the absence of any further dietary manipulations in the daughters in a rat low-protein diet model. Exposure to low-protein grand-maternal diet leads to decreased ovarian reserve and increased intra-abdominal fat mass in granddaughters, accompanied by accelerated accumulation of oxidative stress and mtDNA copy number instability in the ovaries. Ovarian telomere length declines more rapidly in the exposed granddaughters, indicating accelerated ageing in the reproductive tract. Thus, we demonstrate that suboptimal grandmaternal diet during pregnancy accelerates reproductive ageing across subsequent generations. These findings have important implications for understanding both individual rates of decline in fertility with age, and the clinical impact of current global trends towards delayed childbearing.

Figure 1. Effect of grandmaternal diet and offspring age on intra-abdominal fat mass.

Ovarian fat pads were weighed fresh immediately following dissection. Open bars represent results at 3 months of age, gray bars represent results at 6 months of age. Results are expressed as means (SE); n = 7 per group. *denotes p < 0.05, ***denotes p < 0.001.

Figure 2. Effect of grandmaternal diet and offspring age on ovarian reserve.

Open bars represent results at 3 months of age, gray bars represent results at 6 months of age. **denotes p < 0.01, ***denotes p < 0.001 (A) Primordial follicle count per mm³ of ovarian tissue in whole fixed ovaries. (B) Serum levels of Anti-Müllerian hormone (ng/ml).

Figure 3. Effect of grandmaternal diet and offspring age on ovarian levels of 4-HNE, reflecting oxidative stress.

Open bars represent results at 3 months of age, gray bars represent results at 6 months of age. ***denotes p < 0.001.

Figure 4. Effect of grandmaternal diet and offspring age on ovarian mtDNA.

Open bars represent results at 3 months of age, gray bars represent results at 6 months of age. *denotes p < 0.05, ***denotes p < 0.001 (A) MtDNA copy number (ratio to single copy nuclear gene) in ovarian tissue. (B) Expression of Tfam (regulator of mtDNA biosynthesis) in ovarian tissue.

Figure 5. Effect of grandmaternal diet on telomere length at offspring age 6 months.

Light grey bars represent control group, dark gray bars represent recuperated group. *denotes p < 0.05.

Figure 6. Effect of grandmaternal diet on expression of components of the DNA-activated protein kinase (DNA-PK).

Light grey bars represent control group, dark gray bars represent recuperated group. (A) Ku70 expression (B) Ku80 expression (C) DNA-PKcs.