Transgenics in Endocrinology (Contemporary Endocrinology)
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Many of them have been linked to epigenetic modifications of chromatin and aberrant activation or inactivation of specific genes. Most synthetic compounds have not been present in our biosphere until very recently in human and vertebrate evolutionary history. Therefore, biological evolution has not had enough time to evolve mechanisms against the adverse effects of the disruption caused by these chemicals.
The worst scenario is that many of them exert significant epigenetic action; thus, the adverse effects may persist and even be transgenerational. The latter effect should truly raise serious concern about the safe use of such synthetic products in our modern society and their contamination to our environment.
Transgenics in Endocrinology | Martin Matzuk | Springer
One excellent example of such a compound is vinclozolin, a common fungicide used in vineyards and other agricultural settings. It has been shown to cause transgenerational transmission of induced epigenetic changes transmitted through the sperm Anway et al. Several generations of offspring display disorders such as adult-onset male infertility, accelerated aging, abnormal behavior, and increased frequency of prostate disease in aged males. Similarly, the xenoestrogen DES, once used for the treatment of prostate cancer or habitual miscarriages, exhibits chronic toxicity in a manner that can pass its effects to subsequent generations via epigenetic memories Prins Recently, DES has been shown to induce hypermethylation and chromatin repression in miR promoter in breast epithelial progeny derived from mammospheres.
The action of the xenoestrogen can be explained mechanistically by the observation that repressive chromatin marks were recruited to the miR locus along with DNMT1 Hsu et al. BPA is another epigenetically active xenoestrogen. It is widely used in the manufacture of polycarbonated plastics and the epoxy lining of canned food.
BPA was found in the urine of Neonatal exposure of rats to environmentally relevant doses of BPA induced hypermethylation of the promoter of a cAMP-regulating gene Pde4d and overexpression of the gene in the prostate. These aberrant changes were associated with an increase in the risk of developing prostate lesions in the adult rats Ho et al. Notably, a recent study conducted by Lamartiniere et al.
Moreover, maternal exposure of Agouti mice to BPA was shown to decrease CpG methylation in an intracisternal A particle retrotransposon upstream of the Agouti gene in offspring, a change that could be reversed by maternal dietary supplementation with either methyl donors or a phytoestrogen Dolinoy et al. Finally, it is still controversial as to whether early-life exposure would increase risks of obesity and diabetes in later life Ryan et al.
Other estrogenic epigenetic pollutants include polybrominated diphenyl ethers, fire retardants, that reduce global DNA methylation in hippocampal neurons Siddiqi et al. The list provided in Table 6 is by no means complete. We expect that many more untested chemicals or pollutants will be found to disrupt endocrine function through epigenetic mechanisms. Unfortunately, the effects of endocrine disruptors are not readily discerned and often are ignored.
Their long-lasting adverse effects on human health and wildlife are distressing. The fact that many of their effects are observed at very low doses in a nonlinear manner makes it difficult for regulatory agencies to set guidelines. Future research must continue to focus on revealing their actions through the use of high-throughput, unbiased technologies. 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.
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.
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.
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Introduction and background The most simplistic view of an endocrine axis is one that involves the release of a hormone from an endocrine gland, in response to a stimulus, into the circulation. Genetics as a key determinant of endocrine function Genetics is traditionally viewed as the sole factor controlling the differentiation and function of various endocrine axes.
Phenotype plasticity and developmental plasticity: bases of genotype by environment interaction The environment, endogenous or exogenous, plays a highly significant role in determining the function and variability of an endocrine axis. Epigenetic mechanisms that landscape the genome Epigenetic modifications defined as heritable changes in gene function that occur without a change in the nucleotide sequence Bird , Goldberg et al.
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U, unknown or unclear, denotes no or very few papers reported as of 1 August Epigenetic regulation of peptide hormone action Peptide hormones are another major class of hormones, which have a broad spectrum of action, including regulation of energy metabolism e. Multi-dimensional interaction shapes the epigenome landscape at the organismal level: a possible explanation for the etiology of endocrine disorders 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.
Epigenetics in endocrine disruptors Endocrine disruptors are environmental chemicals that mimic hormone or antihormone activities in the endocrine system and disrupt the physiologic function of endogenous hormones.
Table 6 Epigenetic effect of endocrine disruptors Endocrine disruptor a Routes of exposure Major hormonal effect b Epigenetic effect c References Phytoestrogens such as genistein Soybean Estrogenic; anti-estrogenic Hypomethylation of Nsbp1 in uterine; hypomethylation of TERT promoter and chromatin remodeling in MCF-7 cells; BTG3 promoter demethylation and histone modification in prostate cancer Tang et al. 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.
Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported. Cancer Epidemiology, Biomarkers and Prevention 9 — Part A, Molecular and Integrative Physiology — Related Articles.
View in gallery Epigenetics links genetics with the environment in endocrine function. View in gallery DNA methylation and histone modification are two major epigenetic mechanisms that corroborate in regulating endocrine-related gene expression. Roarty K, Rosen JM.