Hormonal Imprinting Research Articles

Effect of a Single Neonatal Oxytocin Treatment (Hormonal Imprinting) on the Biogenic Amine Level of the Adult Rat Brain: Could Oxytocin-Induced Labor Cause Pervasive Developmental Diseases?

Perinatal single-hormone treatment causes hormonal imprinting with lifelong consequences in receptor-binding capacity, hormone production as well as in social and sexual behavior. In the present experiments, newborn rats were treated with a single dose of oxytocin, and the levels of biogenic amines and their metabolites were studied in 8 different brain regions and in the sera when the male and female animals were 4 months old. Both dopaminergic and serotonergic neurotransmission was found to be significantly influenced. The levels of 3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindole acetic acid metabolites decreased in the hypothalamus and striatum. Dopamine, serotonin, norepinephrine, and 5-hydroxytryptophol levels were hardly altered, and there was no difference in the epinephrine levels. The results show that dopamine and serotonin metabolism of hypothalamus and striatum are deeply and lifelong influenced by a single neonatal oxytocin treatment Oxytocin imprinting resulted in decreased dopamine turnover in the hypothalamus and decreased serotonin turnover in the hypothalamus, medulla oblongata, and striatum of females. As the disturbance of brain dopamine and serotonin system has an important role in the development of pervasive developmental diseases (eg, autism) and neuropsychiatric disorders (eg, schizophrenia), the growing number of oxytocin-induced labor as a causal factor, cannot be omitted.

Insulin at a unicellular eukaryote level

The unicellular ciliate, Tetrahymena, has been the main model for studying the hormonal system of unicellular animals. Tetrahymena produce, store, secrete and take up insulin, the hormone being similar to that of mammals, both immunocytochemically and functionally. The plasma membrane and nuclear envelope of Tetrahymena have insulin receptors, which are structurally similar to the mammalian receptor, as it their binding capacity. The cell has also second messengers and signal pathways for insulin. Insulin influences the synthesis of other hormones. The first short encounter between the cell and insulin provokes the hormonal imprinting that alters the function of the cells and is transmitted to the progeny, and can persist for over 1,000 generations, in hormone binding, hormone content, phagocytosis, cell growth and movement. Insulin has a survival function in Tetrahymena and during stress insulin production and binding are elevated. Other protozoa also react to insulin, and the evolutionary aspects are discussed in this review since it is still not appreciated that the hormones are of great antiquity in the animal kingdom.

Hormonal imprinting in the central nervous system: causes and consequences

The notion of the perinatal "hormonal imprinting" has been published at first in 1980 and since that time it spred expansively. The imprintig develops at the first encounter between the developing receptor and the target hormone - possibly by the alteration of the methylation pattern of DNA - and it is transmitted to the progeny generations of the cell. This is needed for the complete development of the receptor's binding capacity. However, molecules similar to the target hormone (hormone-analogues, drugs, chemicals, environmental pollutants) can also bind to the developing receptor, causing faulty imprinting with life-long consequences. This can promote pathological conditions. Later it was cleared that in other critical periods such as puberty, imprinting also can be provoked, even in any age in differentiating cells. The central nervous system (brain) also can be mistakenly imprinted, which durably influences the dopaminergic, serotonergic and noradrenergic system and this can be manifested - in animal experiments - in alterations of the sexual and social behavior. In our modern age the faulty hormonal imprintig is inavoidable because of the mass of medicaments, chemicals, the presence of hormone-like materials (e.g. soya phytosteroids) in the food, and environmental pollutants. The author especially emphasizes the danger of oxytocin, as a perinatal imprinter, as it is used very broadly and can basically influence the emotional and social spheres and the appearance of certain diseases such as auitism, schizophrenia and parkinsonism. The danger of perinatal imprinters is growing, considering their effects on the human evolution.

Hormonal imprinting in the unicellular Tetrahymena: The proto-model of epigenetics

The unicellular ciliate, Tetrahymena has a complete hormonal system. It has receptors for receiving hormones, produces, stores and secretes hormones, similar to mammalian ones and has signal transduction pathways, for transmitting the information given by the hormones. The first encounter with a hormone provokes the hormonal imprinting under the effect of which the further encounters with the same hormone induces altered (usually enhanced) reaction (hormone binding, hormone synthesis, chemoattraction, movement, growth etc.). The effect of imprinting is durable, it can be observed also after 1000 generations, or after one year in non-dividing cells. Receptors of the nuclear envelope also can be imprinted. The plasma membrane receptors provoked by imprinting are similar to the receptors of mammals. Although steroid hormones are not present in Tetrahymena, the production of them and their receptors can be induced by imprinting. The hormonal imprinting is an epigenetic process and inhibition of DNA-methylation alters the imprinting. Hormonal imprinting in Tetrahymena was likely the first epigenetic phenomenon which was justified at cellular level. It is very useful for the unicells, as it helps to avoid dangerous molecules more easily or to find useful ones and by this contributes to the permanence of the population's life.

Verification of epigenetic inheritance in a unicellular model system: multigenerational effects of hormonal imprinting

The unicellular Tetrahymena has receptors for hormones of higher vertebrates, produces these hormones, and their signal pathways are similar. The first encounter with a hormone in higher dose provokes the phenomenon of hormonal imprinting, by which the reaction of the cell is quantitatively modified. This modification is transmitted to the progeny generations. The duration of the single imprinter effect of two representative signal molecules, insulin and 5-HT (5-hydroxytryptamine), in two concentrations (10(-6) and 10(-15) M) were studied. The effects of imprinting were followed in 5 physiological indices: (i) insulin binding, (ii) 5-HT synthesis, (iii) swimming behaviour, (iv) cell growth and (v) chemotaxis in progeny generations 500 and 1000. The result of each index was different from the non-imprinted control functions, growth rate, swimming behaviour and chemotactic activity to insulin being enhanced, while others, e.g. synthesis and chemotactic responsiveness of 5-HT and the binding of insulin were reduced. This means that a function-specific heritable epigenetic change during imprinting occurs, and generally a single encounter with a femtomolar hormone concentration is enough for provoking durable and heritable imprinting in Tetrahymena. The experiments demonstrate the possibility of epigenetic effects at a unicellular level and call attention to the possibility that the character of unicellular organisms has changed through to the present day due to an enormous amount of non-physiological imprinter substances in their environment. The results - together with results obtained earlier in mammals - point to the validity of epigenetic imprinting effects throughout the animal world.

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

In pursuit of scientific excellence: sex matters

the year 2012 marks the 125th anniversary of the American Physiological Society (APS). Throughout its history, APS has been a leader in innovation and excellence in scientific technology, discovery, education, and publication. Consistent with this history, APS is leading the scientific publication

The biological basis and clinical significance of hormonal imprinting, an epigenetic process.

The biological phenomenon, hormonal imprinting, was named and defined by us (Biol Rev, 1980, 55, 47-63) 30 years ago, after many experimental works and observations. Later, similar phenomena were also named to epigenetic imprinting or metabolic imprinting. In the case of hormonal imprinting, the first encounter between a hormone and its developing target cell receptor—usually at the perinatal period—determines the normal receptor-hormone connection for life. However, in this period, molecules similar to the target hormone (members of the same hormone family, synthetic drugs, environmental pollutants, etc), which are also able to bind to the receptor, provoke faulty imprinting also with lifelong—receptorial, behavioral, etc.,—consequences. Faulty hormonal imprinting could also be provoked later in life in continuously dividing cells and in the brain. Faulty hormonal imprinting is a disturbance of gene methylation pattern, which is epigenenetically inherited to the further generations (transgenerational imprinting). The absence of the normal or the presence of false hormonal imprinting predispose to or manifested in different diseases (e.g., malignant tumors, metabolic syndrome) long after the time of imprinting or in the progenies.

The Immuno-Endocrine System: Hormones, Receptors and Endocrine Function of Immune Cells. The Packed-Transport Theory

Immune cells (lymphocytes, monocytes and macrophages, granulocytes and mast cells) produce numerous hormones, store and secrete them. In addition these cells have receptors for hormones and signal transduction pathways. These functions are under the control of the central nervous system (neuro-immune regulation), and there is a dynamic multi-directional interaction within the neuroimmune circuitry. Considering the high amount of immune cells, their hormone production can rival to that of the classical endocrine glands. However, in contrast to the endocrine glands, which are in general mono-producers, 1.) the immune cells are poly-producers, the same cell can produce different hormones at the same time and also poly-receivers, having receptors for different hormones, 2.) immune cells are mobile and can transport the hormones in a packaged form, even though they are able to synthesize and secrete the hormones locally. 3.) immune cells have the capacity to recognize the site where their hormones are needed. It is proposed that under the control of the nervous system immune cells produce hormones for general regulation, for intrasystem regulation and for remote, local regulation. Hormone production is gender dependent. Receptors are affected by hormonal imprinting during the critical developmental periods of target cells and the imprinting influences also the hormone synthesis of immune cells for life. Some hormones can be demonstrated in the nucleus of mast cells, however their function is not known. The knock-out of one hormone's gene disturbs hormone balance in immune cells. The importance of the packed-transport hypothesis is discussed.

Hormonal imprinting – the unforeseeable future

Hormonal imprinting takes place at the first encounter between the developing receptor and the target hormone, perinatally, causing life-long changes in the binding capacity of the receptor and the indexes influenced by it. Perinatal hormonal imprinting is absolutely needed for the maturation of receptor, however, at the same time, molecules similar to the target hormone (related hormones, synthetic drugs acting at receptor level, chemicals, environmental pollutants etc.) can cause faulty imprinting, also with (morphological, biochemical, receptorial, behavioral) consequences for life. Although imprinting is characteristic and inevitable perinatally, it can be provoked in any period of life in developing cells, especially at the weanling and adolescent age (late imprinting). There is no gene mutation during imprinting, however, the methylation pattern of the genes changes and that inherits epigenetically the imprinting, which is manifested in disposition to diseases or in diseases (e.g. tumor formation, metabolic syndrome). Imprinting is inherited between generations that could cause--in the present chemical world--evolutionary consequences. Thus, medicaments or preventive drugs, e.g. pregnancy protecting drugs or oral contraceptive pills should be given cautiously, especially in the critical periods, considering that consequences are manifested always after a long period (sometimes decades) or in the next generations.

Flaxseed supplementation of rats during lactation changes the adiposity and glucose homeostasis of their offspring

Aims The aim of this paper was to evaluate the effects of maternal dietary flaxseed during lactation on endocrine and metabolic factors in the adult offspring. Main methods Lactating rats were divided into: (1) Controls (C), diet containing 20% casein; (2) Flaxseed (F), diet with additional 25% of flaxseed, containing 18.9% protein (13.9% from casein and 5% from flaxseed). The treatment started at birth, day 0 (d0) of lactation, and ended at weaning (d21). After weaning, all pups received a standard laboratory diet until 180 days old. Only male offspring were studied and were sacrificed at 21 or 180 days of age. Body composition was evaluated by carcass analysis. Key findings Offspring from F mothers had higher body mass since lactation until adulthood. At 21 days old, they presented lower total and subcutaneous fat mass, higher leptinemia, lower total cholesterol, lower triacylglycerol and lower insulinemia ( p < 0.05). At 180 days, offspring from F mothers had lower glycemia, higher insulinemia and lower adiponectin ( p < 0.05) concentrations and they did not show any changes in body composition. Significance Maternal intake of flaxseed in the diet during lactation produces early insulin sensitivity and hyperleptinemia; these hormonal imprinting factors could program for selective insulin resistance, since the higher insulin serum concentration was not associated with higher adiposity. These findings, associated with lower serum adiponectin concentration in adulthood, could indicate an increased risk for later development of diabetes mellitus.

Impact of neonatal catecholamine treatment on adult response to vasopressin and norepinephrine.

The present experiments have shown that neonatal imprinting with certain catecholamines had a significant impact on adult vascular adrenergic response, and on adult response to vasopressin as well. This finding not only substantiates the existence of a hormonal imprinting mechanism, but also suggests a certain (receptor-level) interaction between the vasopressin and catecholamine receptors involved in vascular contraction.

Influence of Perinatal Stress on the Hormone Content in Immune Cells of Adult Rats: Dominance of ACTH

Rat dams were stressed by total deprivation of food and water for 48 h just before or directly after delivery and the offspring were studied when adult. The immune cells' hormone content (ACTH, histamine, serotonin, and T(3)) was measured by immunocytochemical flow cytometry. The elevation of ACTH content in males was convincing in each cell type (lymphocytes, monocytes and granulocytes, and mast cells). The change in histamine and T(3) content was inconsistent, while serotonin level did not change at all. As ACTH is the key hormone in the General Adaptation Syndrome, it seems likely that the perinatal stress primarily caused elevation in ACTH level and it was provoking the life-long hormonal imprinting. There was a difference between the reaction of males and females (with males' advance), which points to the gender dependence of the phenomenon. It is important that the effect of stress on the offspring was similar in case of direct (prenatal, in the mother) and indirect (postnatal, transmitted by milk) stress treatment, which calls attention to the danger of stress during this latter period.

Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats. Alterations in the biogenic amine contents of the adult brain

Biogenic amines (norepinephrine, dopamine, homovanillic acid, serotonin and 5-hyroxyindole acetic acid) were measured by HPLC method in adult F1 generation rats’ brain regions (brainstem, hypothalamus, hippocampus, striatum and frontal cortex), whose mothers (P generation) were treated with vitamin A or vitamin D neonatally (hormonal imprinting). Many significant differences were found, related to the maternally untreated controls. In the earlier studied P generation females, vitamin A consistently influenced the serotonerg system (5HIAA), while vitamin D the dopaminerg system (DA or HVA). Vitamin A imprinting always resulted in reduced, while that by vitamin D always in increased tissue levels. In the present case (directly untreated F1 generation) the transgenerational effect was not unidirectional, however biogenic amine tissue levels were strongly disturbed and brain-area dependent. The results call attention to the transgenerational effect of hormonal imprinting in the case of receptor level acting vitamins which are frequently used in the most imprinting-sensitive period (perinatally) of human life and suggests that caution is warranted.

Influence of Neonatal Vitamin A or Vitamin D Treatment on the Concentration of Biogenic Amines and their Metabolites in the Adult Rat Brain

Newborn male rats were treated with a single dose of 3 mg vitamin A (retinol) or 0.05 mg vita-min D (cholecalciferol), and three months later five brain regions (frontopolar cortex, hypothalamus, hippocampus, striatum, and brainstem) were studied for tissue levels of dopamine (DA), serotonin (5HT), and metabolites such as homovanillic acid (HVA), as well as 5-hydroxyindole-3-acetic acid (5HIAA). Vitamin A treatment as hormonal imprinting significantly decreased 5HIAA levels in each brain region. Vitamin D imprinting significantly elevated DA only in the brainstem and HVA levels in striatum and hypothalamus. Present and earlier brain-imprinting results (with brain-produced substances), show that the profound and life-long effect of neonatal hormonal imprinting on neurotransmitter production of the adult brain seems to be well established. As prophylactic treatment with these vitamins is frequent in the perinatal period, the imprinting effect of vitamin A and vitamin D must be taken into consideration.

Effect of neonatal nociceptin or nocistatin imprinting on the brain concentration of biogenic amines and their metabolites

Noradrenaline (NA), dopamine (DA), homovanillic acid (HA), serotonin (5HT) and 5-hydroxyindole acetic acid (5HIAA) content of five brain regions (hypothalamus, hippocampus, brainstem, striatum and frontal cortex) and the cerebrospinal fluid (CSF) was measured in adult (three months old) male and female rats treated neonatally with a single dose of 10 μg nociceptin (NC) or 10 μg nocistatin (NS) for hormonal imprinting. The biogenic amine and metabolite content of cerebrospinal fluid was also determined. In NC treated animals the serotonergic, dopaminergic as well as noradrenergic systems were influenced by the imprinting. The 5HT level increased in hypothalamus, the 5HIAA tissue levels were found increased in hypothalamus. Hippocampus and striatum and the HVA levels increased highly significantly in brainstem. Dopamine level decreased significantly in striatum, however in frontal cortex both noradrenalin and 5HIAA level decreased. Nevertheless, in NS-treated rats decreased NA tissue levels were found in hypothalamus, brainstem and frontal cortex. Decreased DA levels were found in the hypothalamus, brainstem and striatum. NS imprinting resulted in decreased HVA level, but increased one in the brainstem. The 5HT levels decreased in the hypothalamus, brainstem, striatum and frontal cortex, while 5HIAA content of CSF, and frontal cortex decreased, and that of hypothalamus, hippocampus and striatum increased. There was no significant difference between genders except in the 5HT tissue levels of NC treated rats. Data presented show that neonatal imprinting both by NC and NS have long-lasting and brain area specific effects. In earlier experiments endorphin imprinting also influenced the serotonergic system suggesting that during labour release of pain-related substances may durably affect the serotonergic (dopaminergic, adrenergic) system which can impress the animals’ later behavior.

Hormonal imprinting: phylogeny, ontogeny, diseases and possible role in present‐day human evolution

Hormonal (chemical) imprinting which was first observed (and named) by us in the seventies of the last century, is a general biological phenomenon which takes place when the developing receptor meets its target hormone for the first time. Under the effect of imprinting, receptors mature and reach their maximal binding capacity. It also influences the cells' hormone production and different functions depending on receptors and hormones. Hormonal imprinting is present already at the unicellular level causing the development of specific receptors and helping the easier recognition of useful or harmful surrounding molecules. The phenomenon is an important factor in the survival of the species, as the effect of imprinting is transmitted to the progeny cell generations. At the same time it possibly helps the selection of molecules which are suitable for acting as hormones in higher ranked animals. In mammals, hormonal imprinting takes place perinatally and determines the function of receptor-signal-transduction systems as well as hormone production for life. However, there are other critical imprinting periods for continuously developing cells. Excess of the target hormones or presence of foreign molecules which are able to bind to the receptors, provoke faulty imprinting in the critical periods with life-long morphological, biochemical, functional or behavioural consequences. As many receptor-bound foreign molecules are used as medical treatments and many such molecules are present around us and inside us as environmental pollutants, they--causing faulty imprinting--are able to predispose the (human) organism to cardiovascular, endocrine, metabolic and cancerous diseases. It seems likely that this effect is connected with disturbance of DNA methylation process in the critical periods of life. There are some signs of the transgenerational effect of faulty imprinting and this could be manifested in the evolution of humans by an epigenetic route.