An epigenetic association of malformations, adverse reproductive outcomes, and fetal origins hypothesis related effects

Abstract

VACTERL, the prototype for associated congenital anomalies, also has connections with functional issues such as pregnancy losses, prematurity, growth delays, perinatal difficulties, and parental subfertility. This segues into a broader association with similar connections even in the absence of malformations. DNA methylation disturbances in the ovum are a likely cause, with epigenetic links to individual components and to folate effects before conception, explaining diverse fetal and placental findings and providing a link to fetal origin hypothesis-related effects. The association encompasses the following: (1) Pre- and periconceptual effects, with frequent fertility issues and occasional imprinting disorders. (2) Early malformations. (3) Adverse pregnancy outcomes (APOs), as above. (4) Developmental destabilization that resolves soon after birth. This potentiates other causes of association findings, introducing multiple confounders. (5) Long-term fetal origins hypothesis-related risks. The other findings are exceptional when the same malformations have Mendelian origins, supporting a distinct pathogenesis. Expressions are facilitated by one-carbon metabolic issues, maternal and fetal stress, and decreased embryo size. This may be one of the commonest causes of adverse reproductive outcomes, but multifactorial findings, variable onsets and phenotypes, and interactions with multiple confounders make recognition difficult. This association supports VACTERL as a continuum that includes isolated malformations, extends the fetal origins hypothesis, explains adverse effects linked to maternal obesity, and suggests possible interventions.

The etiology of VACTERL association: Current knowledge and hypotheses

“…A second commonly mentioned hypothesis is the idea that VACTERL may be because of epigenetic factors (Lubinsky, ). Recently published data has in fact provided more support about the contributions of these factors to congenital disorders.…”

Evolutionary justifications for human reproductive limitations

“…Aneuploid and genetic fecundity issues are largely maternal, and evidence supports the ovum as the primary source of epigenetic effects [4]. This predilection is not surprising, since reproductive costs fall mainly on the mother with pregnancy, breast feeding, and child rearing [3].…”

“…These specifications are nicely met through epigenetic interactions, as gene expression is modified after conception. Further aspects are discussed elsewhere, with an emphasis, continued here, on DNA methylation, which is far from the only mechanism involved, but which is certainly the best studied [4].…”

“…This can affect fertility and fetal vulnerabilities throughout pregnancy through an association related to 1-carbon metabolism issues, and especially folic acid, that links early and late pregnancy losses, prematurity, growth delays, perinatal difficulties, parental fertility issues, and other adversities as well, with both intrinsic and extrinsic contributions. The primary defect arises in the ovum and reflects decreased folate availability [4].…”

“…It is likely that each of these represents a different selective issue. Evidence of an adaptive response to intermittent food shortages exists for the epigenetic effects [4], and specific alternatives will be presented for each of the others.…”