A major gap in the diagnosis and treatment of reproductive dysfunction (e.g. infertility, pregnancy loss) is the extent to which early life growt and development impacts female reproductive function in adulthood. We propose a "womb to womb" approach to women's reproductive health, suggesting that a woman's reproductive function is rooted in developmental processes that extend back to the prenatal environment provided to her by her own mother. We have recently shown in a nonhuman litter-bearing primate, the common marmoset monkey, that a mother who was a triplet herself loses nearly three times as many offspring to stillbirth as twin females (38% vs. 13%) (Rutherford et al. in revision for PNAS). To develop the womb to womb approach, we propose to track three generations of marmoset females starting with pregnant females, then their daughters from birth to adulthood, and their subsequent first pregnancies. We will use serial measures of body weight and composition, sonograms of uterine growth from birth to adulthood, and biomarkers of energetic, inflammatory, and reproductive status to determine how the daughter's intrauterine development programs their adult reproductive function. Marmoset monkeys are small- bodied primates that achieve sexual maturity by 15 months of age, allowing the direct observation of transgenerational processes in a short period of time. Marmoset monkeys display natural variation in litter size, with twins and triplets being common. Twins represent the "control" phenotype, whereas triplets represent the "programming" phenotype analogous to that exhibited by growth-restricted human neonates. The central hypothesis of this proposal is that triplet females will display suboptimal development of the reproductive system from juvenility into early adulthood. The long-term goal of our research is to understand how adult phenotypes of impaired reproductive function emerge from developmental processes. The translational goal is to identify pre-adult biomarkers to predict adult reproductive dysfunction and pregnancy loss in humans.
Aim 1 of our study addresses the hypothesis that a female marmoset's birth status and energetic status during pregnancy will independently predict her pregnancy success.
In Aim 2 we turn to the daughters of the mothers studied in Aim 1, hypothesizing that females who experienced intrauterine restriction (reflected by low birth weight and/or triplet status) will demonstrate dysfunctional metabolic and reproductive phenotypes during growth and development from birth to sexual maturity.
Aim 3 follows the daughters into their adult reproductive phase, centering on the hypothesis that females who experienced intrauterine restriction will exhibit impaired adult metabolic and reproductive function. Together, the data from the three aims will allow us to determine what role first generation characteristics play in the trajectory of second generation growth and development and the viability of third generation gestations, linking the womb in which a female developed to the womb she provides to her offspring.
Many reproductive disorders, including pregnancy loss, remain difficult to predict and treat, suggesting that we need to approach women's reproductive health in novel ways. Adult health is rooted in developmental events that occur early in life, even as far back as the fetal period. This study aims to track three generations of marmoset monkeys to determine how the womb in which a female develops affects the womb she will provide to her own offspring.
|Rutherford, Julienne N; deMartelly, Victoria A; Layne Colon, Donna G et al. (2014) Developmental origins of pregnancy loss in the adult female common marmoset monkey (Callithrix jacchus). PLoS One 9:e96845|