Epigenetics meets endocrinology

Abstract

Although genetics determines endocrine phenotypes, it cannot fully explain the great variability and reversibility of the system in response to environmental changes. Evidence now suggests that epigenetics, i.e. heritable but reversible changes in gene function without changes in nucleotide sequence, links genetics and environment in shaping endocrine function. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNA, partition the genome into active and inactive domains based on endogenous and exogenous environmental changes and developmental stages, creating phenotype plasticity that can explain interindividual and population endocrine variability. We will review the current understanding of epigenetics in endocrinology, specifically, the regulation by epigenetics of the three levels of hormone action (synthesis and release, circulating and target tissue levels, and target-organ responsiveness) and the epigenetic action of endocrine disruptors. We will also discuss the impacts of hormones on epigenetics. We propose a three-dimensional model (genetics, environment, and developmental stage) to explain the phenomena related to progressive changes in endocrine functions with age, the early origin of endocrine disorders, phenotype discordance between monozygotic twins, rapid shifts in disease patterns among populations experiencing major lifestyle changes such as immigration, and the many endocrine disruptions in contemporary life. We emphasize that the key for understanding epigenetics in endocrinology is the identification, through advanced high-throughput screening technologies, of plasticity genes or loci that respond directly to a specific environmental stimulus. Investigations to determine whether epigenetic changes induced by today's lifestyles or environmental `exposures' can be inherited and are reversible should open doors for applying epigenetics to the prevention and treatment of endocrine disorders.

Heredity and lifestyle in the determination of between-subject variation in thyroid hormone levels in euthyroid men

“…With regard to TH regulation, the expression of the sodium iodide symporter was shown to be regulated by cytosine methylation of its promotor. Besides, epigenetic regulation of TSHR has been demonstrated (49).…”

Evidence for increased tissue androgen sensitivity in neurturin knockout mice

“…Comparable observations of changes in androgen responsiveness have been reported previously in uraemic rats (Handelsman et al 1985b) as well as in humanised mice with variable-length CAG repeats in the AR (Simanainen et al 2011). It is speculated that the latter might be an adaptive phenotype termed ontogenic regression (Handelsman & Dong 1992, Handelsman 2004, for example, by epigenetic modifications, with the promoter activity of androgen-sensitive genes being enhanced to maintain the same activity as ARs operating at higher sensitivity (Zhang & Ho 2011). NTN, GDNF, artemin and persephin comprise a group of structurally related neurotrophic factors belonging to the transforming growth factor-b (TGFb) superfamily (Airaksinen & Saarma 2002).…”

In vitro and in vivo testing methods of epigenomic endpoints for evaluating endocrine disruptors

“…This has been reviewed comprehensively (Zhang and Ho, 2011) and allows the data of Table 3 to be presented as a summary of the state of this field.…”

“…This has also been studied reasonably comprehensively and has been reviewed in detail recently (Zhang and Ho, 2011;LeBaron et al, 2010;Vandegehuchte and Janssen, 2011 …”