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The term “epigenetic” was first coined by Waddington in 1939 to describe diverse reprogramming of the same genetic materials to generate a multicellular organism from a single cell.
Epigenetics has evolved to become the science that explains how the differences in the patterns of gene expression in diverse cells or tissues are executed and inherited. Many psychiatric disorders, such as bipolar disorder and major depression, are episodic and may spontaneously remit.
DNA methylation, a common epigenetic alteration of the cytosine residue in the context of CpG dinucleotides, has long been detected in mammals. Hormones or environmental cues can cause demethylation and de novo methylation to alter the inherited pattern of DNA.
James Phelps, MD is Director of the Mood Disorders Program at Samaritan Mental Health in Corvallis, Ore.
Although a given hormone may travel throughout the body in the bloodstream, it will affect the activity only of its target cells; that is, cells with receptors for that particular hormone. The hormones of the human body can be divided into two major groups on the basis of their chemical structure.
Whereas the amine hormones are derived from a single amino acid, peptide and protein hormones consist of multiple amino acids that link to form an amino acid chain.
Examples of peptide hormones include antidiuretic hormone (ADH), a pituitary hormone important in fluid balance, and atrial-natriuretic peptide, which is produced by the heart and helps to decrease blood pressure. The message a hormone sends is received by a hormone receptor, a protein located either inside the cell or within the cell membrane. The location of steroid and thyroid hormone binding differs slightly: a steroid hormone may bind to its receptor within the cytosol or within the nucleus.
Hydrophilic, or water-soluble, hormones are unable to diffuse through the lipid bilayer of the cell membrane and must therefore pass on their message to a receptor located at the surface of the cell.
The phosphorylation of cellular proteins can trigger a wide variety of effects, from nutrient metabolism to the synthesis of different hormones and other products. Overall, the phosphorylation cascade significantly increases the efficiency, speed, and specificity of the hormonal response, as thousands of signaling events can be initiated simultaneously in response to a very low concentration of hormone in the bloodstream. Importantly, there are also G proteins that decrease the levels of cAMP in the cell in response to hormone binding.
You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response.
The permissive effect, in which the presence of one hormone enables another hormone to act. The synergistic effect, in which two hormones with similar effects produce an amplified response. To prevent abnormal hormone levels and a potential disease state, hormone levels must be tightly controlled. Humoral stimuli are changes in blood levels of non-hormone chemicals, such as nutrients or ions, which cause the release or inhibition of a hormone to, in turn, maintain homeostasis. An endocrine gland may also secrete a hormone in response to the presence of another hormone produced by a different endocrine gland.
In addition to these chemical signals, hormones can also be released in response to neural stimuli.
Bisphenol A and Endocrine Disruption You may have heard news reports about the effects of a chemical called bisphenol A (BPA) in various types of food packaging.
Research suggests that BPA is an endocrine disruptor, meaning that it negatively interferes with the endocrine system, particularly during the prenatal and postnatal development period. The potential harmful effects of BPA have been studied in both animal models and humans and include a large variety of health effects, such as developmental delay and disease. A newly developed pesticide has been observed to bind to an intracellular hormone receptor.
A student is in a car accident, and although not hurt, immediately experiences pupil dilation, increased heart rate, and rapid breathing.
Compare and contrast the signaling events involved with the second messengers cAMP and IP3. In both cAMP and IP3–calcium signaling, a hormone binds to a cell membrane hormone receptor that is coupled to a G protein. Describe the mechanism of hormone response resulting from the binding of a hormone with an intracellular receptor.
The smooth endoplasmic reticulum is like a little factory inside the cells of animals and plants. Add important lessons to your Custom Course, track your progress, and achieve your study goals faster. 2.Draw a sketch of a chloroplast and indicate where these energy transformations take place. 3.List the inputs (raw materials) and outputs (products) of the light reactions and the Calvin Cycle. 4.Describe the role of ADP, ATP, NADP, and NADPH in linking the light reactions and Calvin Cycle.
Professor Govindjee, here at UIUC, is one of the leaders in the field of photosynthesis research and education. Photosynthesis Problem Set 1 The objectives of this problem set are to test your understanding of how light energy isconverted into different forms of chemical energy during photosynthesis, to review theequations for the light reactions of photosynthesis, to study the pathway for electron transportduring cyclic and non-cyclic photophosphorylation, and to explore the mechanism forcoupling electron transport to ATP synthesis. Photosynthesis Problem Set 2 The objectives for this problem set are to review the location and overall reactions of carbohydrate biosynthesis during photosynthesis, including RUBISCO, and to understand the difference between C3 and C4 plant leaf anatomy and pathways for carbohydrate biosynthesis. With new technologies and knowledge, several types of epigenetic modifications—such as DNA methylation, histone modifications, RNA editing, and RNA interference—have been discovered. Although heritable, epigenetic programming is influenced by micro and macro environmental factors, and it provides a short-term and generation-specific cellular memory to adapt to variable conditions.
The episodic nature of these diseases suggests that they are unlikely to be pure genetic diseases, which in general are responsible for the genesis of life-long illness. The common types of epigenetic modifications are discussed in brief, to provide a rationale for their suitability to design therapeutics.
Methylated CpGs are targets for DNA-binding domain proteins such as MBD1, MBD3, MBD4, and MeCP2, which correspond to silencing of gene expression, genomic imprinting, suppression of transposable elements, and X inactivation in females. Once the hormone binds to the receptor, a chain of events is initiated that leads to the target cell’s response. An example of a hormone derived from tryptophan is melatonin, which is secreted by the pineal gland and helps regulate circadian rhythm.
Peptide hormones consist of short chains of amino acids, whereas protein hormones are longer polypeptides. Some examples of protein hormones include growth hormone, which is produced by the pituitary gland, and follicle-stimulating hormone (FSH), which has an attached carbohydrate group and is thus classified as a glycoprotein. Because blood is water-based, lipid-derived hormones must travel to their target cell bound to a transport protein.

The receptor will process the message by initiating other signaling events or cellular mechanisms that result in the target cell’s response. The response may include the stimulation of protein synthesis, activation or deactivation of enzymes, alteration in the permeability of the cell membrane, altered rates of mitosis and cell growth, and stimulation of the secretion of products. In either case, this binding generates a hormone-receptor complex that moves toward the chromatin in the cell nucleus and binds to a particular segment of the cell’s DNA. Except for thyroid hormones, which are lipid-soluble, all amino acid–derived hormones bind to cell membrane receptors that are located, at least in part, on the extracellular surface of the cell membrane.
In the cAMP second messenger system, a water-soluble hormone binds to its receptor in the cell membrane (Step 1 in [link]). The effects vary according to the type of target cell, the G proteins and kinases involved, and the phosphorylation of proteins.
However, the duration of the hormone signal is short, as cAMP is quickly deactivated by the enzyme phosphodiesterase (PDE), which is located in the cytosol. For example, when growth hormone–inhibiting hormone (GHIH), also known as somatostatin, binds to its receptors in the pituitary gland, the level of cAMP decreases, thereby inhibiting the secretion of human growth hormone. For example, thyroid hormones have complex permissive relationships with certain reproductive hormones. Positive feedback loops are characterized by the release of additional hormone in response to an original hormone release. Negative feedback is characterized by the inhibition of further secretion of a hormone in response to adequate levels of that hormone.
These reflexes may be simple, involving only one hormone response, or they may be more complex and involve many hormones, as is the case with the hypothalamic control of various anterior pituitary–controlled hormones. For example, osmoreceptors in the hypothalamus detect changes in blood osmolarity (the concentration of solutes in the blood plasma). Such hormonal stimuli often involve the hypothalamus, which produces releasing and inhibiting hormones that control the secretion of a variety of pituitary hormones. A common example of neural stimuli is the activation of the fight-or-flight response by the sympathetic nervous system.
In particular, BPA mimics the hormonal effects of estrogens and has the opposite effect—that of androgens. For example, prenatal exposure to BPA during the first trimester of human pregnancy may be associated with wheezing and aggressive behavior during childhood.
A hydrophobic hormone diffuses through the cell membrane and binds to the intracellular hormone receptor, which may be in the cytosol or in the cell nucleus.
Read more about this fascinating structure and how it makes and distributes the products that cells need to function correctly. These modifications are involved in the regulation of gene expression without changing the sequence of DNA. A multitude of genome-wide association scans of thousands of patients with schizophrenia or bipolar disorder and controls have revealed that while genetic mutations of hundreds of genes appear to be associated with severe mental illness, the effective contribution of each gene is very small (1% to 2%).1 This, along with the fact that the majority of affected individuals do not exhibit any single pattern of genetic mutations, implies that major psychiatric disorders are multifactorial and may involve epigenetic alterations. In the early embryonic stage, DNA methylation marks are erased to generate virtual totipotent cells that then acquire a tissue-specific epigenome that defines the identity and destination of the differentiated cells.
Interestingly, in the brain, a significant fraction of the methylated cytosines are in fact 5hmC and correspond to the induction of gene expression. Hormones play a critical role in the regulation of physiological processes because of the target cell responses they regulate. Tyrosine derivatives include the metabolism-regulating thyroid hormones, as well as the catecholamines, such as epinephrine, norepinephrine, and dopamine. Both types are synthesized like other body proteins: DNA is transcribed into mRNA, which is translated into an amino acid chain.
For example, the reproductive hormones testosterone and the estrogens—which are produced by the gonads (testes and ovaries)—are steroid hormones. This more complex structure extends the half-life of steroid hormones much longer than that of hormones derived from amino acids. Hormone receptors recognize molecules with specific shapes and side groups, and respond only to those hormones that are recognized. Steroid hormones are derived from cholesterol and therefore can readily diffuse through the lipid bilayer of the cell membrane to reach the intracellular receptor ([link]). Therefore, they do not directly affect the transcription of target genes, but instead initiate a signaling cascade that is carried out by a molecule called a second messenger. This receptor is associated with an intracellular component called a G protein, and binding of the hormone activates the G-protein component (Step 2).
The action of PDE helps to ensure that a target cell’s response ceases quickly unless new hormones arrive at the cell membrane.
In this system, G proteins activate the enzyme phospholipase C (PLC), which functions similarly to adenylyl cyclase.
For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. A dietary deficiency of iodine, a component of thyroid hormones, can therefore affect reproductive system development and functioning.
For example, two different reproductive hormones—FSH from the pituitary gland and estrogens from the ovaries—are required for the maturation of female ova (egg cells). Insulin increases the liver’s storage of glucose as glycogen, decreasing blood glucose, whereas glucagon stimulates the breakdown of glycogen stores, increasing blood glucose.
Feedback loops govern the initiation and maintenance of most hormone secretion in response to various stimuli.
If blood osmolarity is too high, meaning that the blood is not dilute enough, osmoreceptors signal the hypothalamus to release ADH. When an individual perceives danger, sympathetic neurons signal the adrenal glands to secrete norepinephrine and epinephrine.
Common food-related items that may contain BPA include the lining of aluminum cans, plastic food-storage containers, drinking cups, as well as baby bottles and “sippy” cups.
Adults exposed to high levels of BPA may experience altered thyroid signaling and male sexual dysfunction. Hydrophobic hormones are able to diffuse through the membrane and interact with an intracellular receptor. In the case of cAMP signaling, the activated G protein activates adenylyl cyclase, which causes ATP to be converted to cAMP. In fact, while genetic codes determine the structure of proteins, epigenetic codes define the time, duration, and amount of protein synthesis in a specific cell or tissue. This dynamic pattern of gene regulation might be a response to internal cues (eg, hormones, neurotransmitters, cellular metabolic states) as well as external cues (eg, neuronal activation, climate changes, seasons, drugs, malnutrition, contaminants).
Any interference in the process, including the unavailability of the various factors or nutrients (eg, methyl groups, folic acid) may result in an aberrant DNA methylome in the derivative cells. These responses contribute to human reproduction, growth and development of body tissues, metabolism, fluid, and electrolyte balance, sleep, and many other body functions.

These chemical groups affect a hormone’s distribution, the type of receptors it binds to, and other aspects of its function. Epinephrine and norepinephrine are secreted by the adrenal medulla and play a role in the fight-or-flight response, whereas dopamine is secreted by the hypothalamus and inhibits the release of certain anterior pituitary hormones.
The adrenal glands produce the steroid hormone aldosterone, which is involved in osmoregulation, and cortisol, which plays a role in metabolism.
A hormone’s half-life is the time required for half the concentration of the hormone to be degraded.
The same type of receptor may be located on cells in different body tissues, and trigger somewhat different responses. Thyroid hormones, which contain benzene rings studded with iodine, are also lipid-soluble and can enter the cell.
For both steroid and thyroid hormones, binding of the hormone-receptor complex with DNA triggers transcription of a target gene to mRNA, which moves to the cytosol and directs protein synthesis by ribosomes. The activated G protein in turn activates an enzyme called adenylyl cyclase, also known as adenylate cyclase (Step 3), which converts adenosine triphosphate (ATP) to cAMP (Step 4). Once activated, PLC cleaves a membrane-bound phospholipid into two molecules: diacylglycerol (DAG) and inositol triphosphate (IP3).
This process is called downregulation, and it allows cells to become less reactive to the excessive hormone levels.
The initial release of oxytocin begins to signal the uterine muscles to contract, which pushes the fetus toward the cervix, causing it to stretch. An example of a negative feedback loop is the release of glucocorticoid hormones from the adrenal glands, as directed by the hypothalamus and pituitary gland. The hormone causes the kidneys to reabsorb more water and reduce the volume of urine produced.
The two hormones dilate blood vessels, increase the heart and respiratory rate, and suppress the digestive and immune systems. Other uses of BPA include medical equipment, dental fillings, and the lining of water pipes. Food and Drug Administration (FDA) notes in their statement about BPA safety that although traditional toxicology studies have supported the safety of low levels of exposure to BPA, recent studies using novel approaches to test for subtle effects have led to some concern about the potential effects of BPA on the brain, behavior, and prostate gland in fetuses, infants, and young children. BPA exposure during the prenatal or postnatal period of development in animal models has been observed to cause neurological delays, changes in brain structure and function, sexual dysfunction, asthma, and increased risk for multiple cancers. This second messenger can then initiate other signaling events, such as a phosphorylation cascade. This initiates the transcription of a target gene, the end result of which is protein assembly and the hormonal response. Some epigenetic changes induced by external cues can be transferred to next generation, leading to a disease state. For example, the lipid-derived hormone cortisol has a half-life of approximately 60 to 90 minutes.
Thus, the response triggered by a hormone depends not only on the hormone, but also on the target cell. As the second messenger, cAMP activates a type of enzyme called a protein kinase that is present in the cytosol (Step 5). When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors.
This, in turn, signals the pituitary gland to release more oxytocin, causing labor contractions to intensify.
As glucocorticoid concentrations in the blood rise, the hypothalamus and pituitary gland reduce their signaling to the adrenal glands to prevent additional glucocorticoid secretion ([link]). This reabsorption causes a reduction of the osmolarity of the blood, diluting the blood to the appropriate level.
These responses boost the body’s transport of oxygen to the brain and muscles, thereby improving the body’s ability to fight or flee. In vitro studies have also shown that BPA exposure causes molecular changes that initiate the development of cancers of the breast, prostate, and brain. These are typically associated with a G protein, which becomes activated when the hormone binds the receptor. Hormonal stimuli are changes in hormone levels that initiate or inhibit the secretion of another hormone. In the case of IP3–calcium signaling, the activated G protein activates phospholipase C, which cleaves a membrane phospholipid compound into DAG and IP3. In contrast, the amino acid–derived hormone epinephrine has a half-life of approximately one minute. Activated protein kinases initiate a phosphorylation cascade, in which multiple protein kinases phosphorylate (add a phosphate group to) numerous and various cellular proteins, including other enzymes (Step 6). At the same time, IP3 causes calcium ions to be released from storage sites within the cytosol, such as from within the smooth endoplasmic reticulum.
Many US companies have voluntarily removed BPA from baby bottles, “sippy” cups, and the linings of infant formula cans, and most plastic reusable water bottles sold today boast that they are “BPA free.” In contrast, both Canada and the European Union have completely banned the use of BPA in baby products.
Although these studies have implicated BPA in numerous ill health effects, some experts caution that some of these studies may be flawed and that more research needs to be done. This initiates a signaling cascade that involves a second messenger, such as cyclic adenosine monophosphate (cAMP).
Finally, a neural stimulus occurs when a nerve impulse prompts the secretion or inhibition of a hormone. The calcium ions then act as second messengers in two ways: they can influence enzymatic and other cellular activities directly, or they can bind to calcium-binding proteins, the most common of which is calmodulin.
High blood glucose levels cause the release of insulin from the pancreas, which increases glucose uptake by cells and liver storage of glucose as glycogen. In the meantime, the FDA recommends that consumers take precautions to limit their exposure to BPA.
Second messenger systems greatly amplify the hormone signal, creating a broader, more efficient, and faster response.
In addition to purchasing foods in packaging free of BPA, consumers should avoid carrying or storing foods or liquids in bottles with the recycling code 3 or 7. Examples of hormones that use calcium ions as a second messenger system include angiotensin II, which helps regulate blood pressure through vasoconstriction, and growth hormone–releasing hormone (GHRH), which causes the pituitary gland to release growth hormones. Foods and liquids should not be microwave-heated in any form of plastic: use paper, glass, or ceramics instead.

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