In utero life and epigenetic predisposition for disease

Abstract

Regulatory regions of the human genome can be modified through epigenetic processes during prenatal life to make an individual more likely to suffer chronic diseases when they reach adulthood. The modification of chromatin and DNA contributes to a larger well-documented process known as "programming" whereby stressors in the womb give rise to adult onset diseases, including cancer. It is now well known that death from ischemic heart disease is related to birth weight; the lower the birth weight, the higher the risk of death from cardiovascular disease as well as type 2 diabetes and osteoporosis. Recent epidemiological data link rapid growth in the womb to metabolic disease and obesity and also to breast and lung cancers. There is increasing evidence that "marked" regions of DNA can become "unmarked" under the influence of dietary nutrients. This gives hope for reversing propensities for cancers and other diseases that were acquired in the womb. For several cancers, the size and shape of the placenta are associated with a person's cardiovascular and cancer risks as are maternal body mass index and height. The features of placental growth and nutrient transport properties that lead to adult disease have been little studied. In conclusion, several cancers have their origins in the womb, including lung and breast cancer. More research is needed to determine the epigenetic processes that underlie the programming of these diseases.

Figure 3.1

Flow diagram illustrating the process of programming. Developmental plasticity allows a number of gene expression options during development. Stressors like malnutrition, excess cortisol, or hypoxia may lead to changes in gene expression in the embryo that predispose the offspring to disease in later life. The effect on the fetus will depend on its gender, its stage of gestation, the nutrient environment, and its genetic background. Female offspring may give birth to offspring that are programmed, repeating the cycle in the next generation.

Figure 3.2

A summary of one-carbon metabolism and its role in DNA methylation (adapted from Johnson and Belshaw, 2008).

Figure 3.3

Proposed model for folate transport across human placental syncytiotrophoblast. Folate receptor alpha (FRa), localized to the microvillous membrane (MVM) surface binds 5-MTHF (folate). Colocalization of FRa and PCFT to MVM allows internalization of both transporters into an endosomal structure. Following acidification of the endosome by vacuolar proton ATPase, a favorable H⁺ gradient exists allowing the H⁺-coupled movement of folate by PCFT into the cytoplasm. FRa and PCFT are then recycled back to the MVM surface. RFC at the MVM surface provides an alternative folate uptake mechanism which would be favored at physiological pH. Efflux across the BM does not involve FRa or PCFT. Instead, folate is transported across BM via an exchange mechanism by RFC. Other transport mechanisms localized to BM may also play a role in transporting folate across the basal plasma membrane. From Solankey et al. (2004) with permission.