https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071959/?fbclid=IwAR2xtUPKnqazgKP0vavon2wq8_0Pup64aKCkRMtpIYFQ7LNyUrS9LaMNe0k
Excerpts from “Epigenetics meets endocrinology” by Xiang Zhang and Shuk-Mei Ho
...1.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.
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2.The inherited variability is static and does not change in response to the environment. The acquired variability can be caused by an environmental factor such as u.v. radiation from the sun (exogenous) or reactive oxygen species generated during metabolism (endogenous). But once acquired these effects are permanent and irreversible. Thus, inherited and acquired variability, either alone or in concert, cannot fully explain the high degree of variability and the reversibility of the endocrine system in response to the environment.
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3. Most cells or organs have various degrees of phenotypic plasticity, whereby the phenotype expressed by a genotype is dependent on environmental influences
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Collectively, these findings indicate that nongenetic factors, including the environment, are important determinants of variability in endocrine function and risk of disorders. Endocrine glands and their target organs, because they function to maintain homeostasis in the body, must be highly responsive to environmental changes.
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4. A high degree of mismatch between the adaptive trait and the future environment, which includes aging, changes in lifestyle, or the introduction of new chemicals, pathogens, and pollutants, may increase the risk of developing disease. Prime examples are the strong correlations observed between hyponutrition and/or low birth weight with many endocrine disorders related to thyroid function, calcium balance, utilization of glucose, insulin sensitivity, and adrenal gland function (Vaag & Poulsen 2007, Hyman et al. 2009, Latini et al. 2009).
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5. The mechanisms underlying the interactions of genetics and the environment, which produce an adaptive phenotype in an endocrine axis, remain elusive. However, a growing body of literature suggests that the missing connection resides in epigenetics, a pivotal mechanism of interactions between genes and the environment (Jaenisch & Bird 2003, Cook et al. 2005, Jirtle & Skinner 2007, Tang & Ho 2007, Vaag & Poulsen 2007, Ling & Groop 2009; Fig. 1).
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6. Epigenetics links genetics with the environment in endocrine function. Hormone levels vary in response to internal and external environmental changes. Epigenetics, in response to exogenous and endogenous environmental cues, defines active and repressed domains of the genome. These responses explain the high phenotypic plasticity observed in the endocrine system, in which different genetic programs are executed from the same genome based on changes in the environment.
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7. Epigenetic modifications defined as heritable changes in gene function that occur without a change in the nucleotide sequence (Bird 2007, Goldberg et al. 2007, Berger et al. 2009). They are mitotically and transgenerationally inheritable (Rakyan et al. 2002, 2003, Hitchins et al. 2007) and potentially reversible (Bannister & Kouzarides 2005, Weaver et al. 2005). The most studied mechanisms known to affect the epigenome are DNA methylation, histone modification, and aberrant expression of microRNAs (miRNAs; Esteller 2005). These processes along with other epigenetic events determine when and whether various sets of genes are expressed in a tissue or cell.
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8. Histones are special proteins that facilitate the packaging of the DNA into nucleosomes, the basic building block of the chromatin. Posttranslational modifications such as acetylation, methylation, phosphorylation, sumoylation, and ubiquitination occur at specific residues in histones N-terminal tails (Cosgrove et al. 2004). These modifications determine whether the DNA wrapped around histones is accessible to the transcriptional machinery... In most instances, histone modifications work hand-in-hand with DNA methylation to achieve short- and long-term changes in transcriptional programs through transient or permanent reorganization of the chromatin architecture (Kondo 2009; Fig. 2).
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9. DNA methylation and histone modification are two major epigenetic mechanisms that corroborate in regulating endocrine-related gene expression. Packaging genes into active or inactive chromatin determines whether they are transcriptionally accessible or not. The N-termini of histones have specific amino acids that are sensitive to posttranslational modifications, which contribute to chromatin status.
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10. Epigenetics also plays important roles in regulating thyroid hormone and retinoic acid metabolism. For example, the expression of the sodium iodide symporter (SLC5A5), which is responsible for the uptake of iodine in the thyroid, was shown to be regulated by cytosine methylation of its promoter (Venkataraman et al. 1999, Smith et al. 2007).
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11. As a general observation, epigenetic dysregulation of the expression of type I receptor genes is closely linked to endocrine-related disorders including cancers of the breast, prostate, testis, and endometrium. DNA methylation dysregulates androgen receptor expression in prostate and endometrial cancer (Kinoshita et al. 2000, Sasaki et al. 2000), estrogen receptor-α in breast cancer (Yoshida et al. 2000, Archey et al. 2002, Adams et al. 2007, Champagne & Curley 2008), estrogen receptor-β in ovarian, prostate, and breast cancer (Zhao et al. 2003, Zhu et al. 2004, Zhang et al. 2007, Zama & Uzumcu 2009), and progesterone receptor in endometrial cancer (Sasaki et al. 2003).
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12. Peptide hormones are another major class of hormones, which have a broad spectrum of action, including regulation of energy metabolism (e.g. insulin), adiposity (e.g. leptin), growth (e.g. GH), and differentiation (e.g. FSH).
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Disruption of the synthesis of peptide hormones or their cognate receptors by epigenetic events often leads to metabolic changes (e.g. obesity and metabolic syndrome; Plagemann et al. 2009) and abnormalities in neuropsychological behavior (e.g. autism and alcohol dependence; Gregory et al. 2009, Hillemacher et al. 2009), as opposed to cancer, the predominant disorder for epigenetic dysregulation of steroid hormones and their receptors (Widschwendter et al. 2004).
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...Notably, epigenetic regulation of genes encoding peptide hormones or their receptors is largely related to developmental stage- and tissue-specific function or the development of a metabolic or neural disorder. For example, in cultures of mouse embryonic stem cells, the hypermethylated promoter of the insulin gene undergoes demethylation as these cells differentiate into hormone-producing cells; and in both the mouse and human insulin gene promoters, the CpG sites are demethylated in insulin-producing pancreatic β-cells but not in other tissues without insulin expression (Kuroda et al. 2009).
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13. In a recent study of autism-spectrum disorders, hypermethylation of the gene promoter encoding the oxytocin receptor was found to be associated with a reduced level of mRNA expression and was significantly associated with autism (Gregory et al. 2009). In another report, significant alterations of the mRNA expression and promoter-related DNA methylation of vasopressin were reported in patients with alcohol dependence (Hillemacher et al. 2009).
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At the organismal level, the functioning of an endocrine axis involves multiple endocrine organs: for example, the hypothalamo–pituitary-gonadal axis comprising at least three hormone-producing tissues and many target tissues. The coordination of the entire axis, representing the first dimension of regulation controlled by genetic programs, is complex and meticulously well controlled. The interaction of these programs with the environment produces variable epigenomes, greatly amplifying the complexity of interaction and outcomes. These interactions can be viewed as the second dimension of influence...Finally, we will emphasize the effects of lifespan events that have strong modifying influences on epigenetics and pay special attention to windows of susceptibility during human development from conception to death.
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14. Genetics, environment, and stages of lifespan development interact in a three-dimensional space to create discordant endocrine phenotypes (epigenomes) from an identical genetic background (a single genome).
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A widely studied area of epigenetics–environment– lifespan interactions is the relationship between birth weight and disease in later life. Animal studies have demonstrated that retardation of intrauterine growth results in progressive loss of β-cell function and the eventual development of type 2 diabetes in the adult. This association directly links chromatin remodeling with suppression of gene transcription (Simmons 2009).
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15. A review of human studies also indicated an inverse relationship between birth weight and susceptibility to endocrine metabolic disorders such as insulin resistance, type 2 diabetes, hyperlipidemia, and obesity (Godfrey 2006).
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Insulin resistance is another example of epigenetic dysregulation resulting in the loss of function in an endocrine axis over time when it is constantly challenged by environmental changes such as specific dietary deficits. It is the condition in which normal amounts of insulin are insufficient to produce a normal insulin response from insulin-sensitive organs/tissues such as the liver, muscle, and adipose tissue, which all play an important role in the etiology and clinical course of patients with type 2 diabetes, high blood pressure, or coronary heart disease (Reaven 1993).
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16. Summary and perspectives
It has become apparent that genetics alone is insufficient to explain the dynamic and complex interdependent relationships between the endocrine system and endogenous and exogenous environmental changes. Genetics alone also fails to address issues related to the progressive changes in endocrine functions over an individual's lifespan, the early origin of endocrine disorders, phenotype discordance between MZ twins, and rapid shifts in disease patterns among populations experiencing major changes in lifestyle, such as immigration. Mounting evidence now suggests that epigenetics is the missing link between genetics, the environment, and endocrine function. In this regard, genetics provides a basis for epigenetic modifications and a blueprint for hormone action. However, the great variability in endocrine function and susceptibility to endocrine-related diseases among individuals or populations is clearly determined by epigenetics. Epigenetics serves as a mechanism mediating the continuous `editing' of the genome or epigenetic marks laid down in early life by exposures and experiences during later life. This paradigm has expanded the static and gene-centric view of phenotypic attributes to a more plastic and adaptive view molded by epigenetics. To fully understand the impacts of epigenetics on endocrine function and vice versa, we need a genome-wide search for plasticity genes or loci directly responsive to a specific environmental stimulus. To achieve this goal, current research is applying high-throughput investigative technologies to uncover global changes in the methylome(s), miRNA signatures, and the histone codes defining the interplay and advanced informatics to produce biologically meaningful data and conclusions. To advance these investigations, our focus should be placed on two commonly raised questions: 1) whether epigenetic changes induced by environmental exposures or lifestyle choices in one generation can be passed to the next and 2) whether these `inherited' changes can be reversed upon removal of the exposures or through lifestyle modifications. Answers to the first question are of paramount importance to the primary prevention of endocrine disorders such as obesity, and answers to the second would open doors to the use of epigenetic drugs or interventions for the reversal of endocrine disorders with a strong epigenetic etiology. The opportunities of applying epigenetics to the prevention and treatment of endocrine disorders are limitless and certainly will emerge rapidly in the near future.
