Parental programming: How can we improve study design to discern the molecular mechanisms?

Abstract

The contribution of inherited non-genetic factors to complex diseases is of great current interest. The ways in which mothers and fathers can affect their offspring's health clearly differ as a result of the intimate interactions between mother and offspring during pre- and postnatal life. There is, however, potential for some overlap in mechanisms, particularly epigenetic mechanisms. A small number of epidemiological studies and animal models have investigated the non-genetic contribution of the parents to offspring health. Discovering new mechanisms of disease inheritance is technically difficult, especially in genetically, socially and environmentally heterogeneous human populations. Therefore, rigorous experimental design, appropriate sample numbers and the use of high-throughput technologies are necessary to provide convincing evidence. Based on recent examples from the literature, here we propose several ways to improve human studies that aim to identify the underlying mechanisms of transgenerational inheritance of metabolic disease.

Relationships of maternal and paternal anthropometry with neonatal body size, proportions and adiposity in an Australian cohort

“…The extent to which relationships between parental and offspring anthropometry are genetic, epigenetic or phenotypic in origin is currently unclear. Epigenetics may play an important role in associations between paternal and offspring metabolism (Kaati et al, 2002;Pembrey, 2002;Lecomte et al, 2013;Wells, 2014), and could also link to prenatal growth. For example, Soubry et al (2013) recently showed that paternal obesity was associated with hypomethylation of IGF2, an important regulator of prenatal growth.…”

A paternal environmental legacy: Evidence for epigenetic inheritance through the male germ line

“…Since the fathers were likely to be exposed to the same famine or nutritional conditions as the mothers, a paternal effect cannot be excluded in these cohorts. As suggested by Lecomte et al [106], large epidemiological studies are needed where stratified analyses by maternal and paternal influences are carried out, and attempts to dissociate parental obesity from nutritional status should help us understand which phenotype is related to which nutrient deficiency or abundance. Finally, an extensive nutritional study on multiple populations was published in 1939 by Weston Price, an American nutritionist and dentist who investigated multiple tribal diets around the world [107].…”

Effects of paternal obesity on growth and adiposity of male rat offspring

“…In human studies, it is often difficult to discriminate between the role of paternal preconception metabolic status and the influence of a shared unhealthy lifestyle between parents and offspring. Furthermore, it is rare that only one parent is obese or overweight; thus it is difficult in the human situation to study paternal obesity in isolation (32). To this end, we developed a model of diet-induced paternal obesity in the rat and were the first to show a direct impact of paternal obesity; female offspring from high-fat diet (HFD)-fed fathers developed glucose intolerance from 6 wk of age (42), which is linked to a defect in insulin secretion by pancreatic islets in response to glucose.…”