Overview of The Fetal Origins of Adult Disease and The Role of The Obstetrician-Gynecologist in Predictive Health
By Sarah Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, is Associate Editor for OB/GYN Clinical Alert
Dr. Berga reports no financial relationship to this field of study.
The two main modifiers of pathogenesis are age and sex. Reversible and irreversible modifications to cellular machinery through genetic and epigenetic mechanisms begin with embryogenesis. For instance, certain aspects of in vitro culture conditions "imprint" genetically normal embryos by altering methylation patterns and gene expression. An increase incidence of imprinting syndromes such as Beckwith-Wiederman has been described in the offspring conceived via in vitro fertilization and embryo transfer (assisted reproduction). Further, imprinting disorders are differentially expressed in male and female offspring due to mechanisms involving both hormone-dependent and hormone-independent gene regulation and expression. This notion is articulated in the field of reproductive endocrinology when we refer to ourselves as "gamete doctors" and in traditional obstetrics when we view ourselves as "fetal doctors." Naturally, both of these labels raise ancient ethical dilemmas regarding the balancing of maternal and paternal health interests with embryo and fetal health interests. Of note, the children of older fathers appear to have an increase in offspring with imprinting and autosomal dominant disorders, indicating that the genome not only is dynamically modified by a variety of specified and unspecified factors having to do with sex, age, and lifestyle, but that these changes may be transmitted to the next generation by either parent.
Traditional modifiers of gamete, embryo, and fetal health include a host of maternal and paternal factors, some of which are under sociocultural control, including stress, nutrition, infectious disease, and environmental exposures. For instance, maternal stress and disease alter cortisol and thyroxine rhythms and levels, which in turn modulate DNA methylation patterns in the fetus. Since the mother is the sole source of thyroxine for the developing fetal brain in the first trimester and the predominant source in the second and third trimesters, seemingly innocent alterations in thyroid function induced by disease, stress, or undernutrition may impact fetal neurodevelopment and predispose to adult neuropsychiatric disease. Some have hypothesized that subtle factors such as these underlie autism spectrum disorders, schizophrenia, and mood disorders.
In the field of obstetrics, the fetal origins of adult disease is a hot topic. There is interest in identifying modifiable factors to guide public health policy and in mechanisms of disease that might be harnessed to identify or prevent disease. For instance, we already employ pre-implantation genetic diagnosis to identify known genetic disease in embryos prior to embryo transfer. This is routinely used for carriers of cystic fibrosis. Also, there is great interest in understanding why male and female embryos appear to be differentially sensitive to certain insults. Further, somewhat unexpectedly, monozygotic twins were found to acquire epigenetic differences as they age such that they diverge in terms of gene expression and disease predilection across their lifespans. Ultimately, it is expected that these fields of inquiry and investigation will contribute to the ongoing debate about the role of medicine and government in preventing disease and promoting better societal and global health. Research in these areas will lead to better ways to harness the promise of molecular medicine for the interests of individuals and society.
- Bjornsson HT,et al. JAMA. 2008;299:2877-2883.
- Fraga MF, et al. PNAS. 2005;102:10604-10609.
- Gabellini D, et al. Curr Opin Genet Dev. 2004;3:301-307.
- Jablonka E. Intl J of Epidemiol. 2004;33:929-935.
- Makedonski K, et al. Hum Mol Genet. 2005;14:1049-1058.
- Ogawa Y, et al. Science. 2008; 320:1336-1341.
- Zardi G, et al. Cell Res. 2005;15:679-690.