Possible contribution of trained immunity in faulty hormonal imprinting and DOHaD: Review and hypothesis.

The faulty hormonal imprinting theory (published in 1980) and the DOHaD (Developmental Origin of Health and Disease theory (published in 1986) are twin-concepts: both justify the manifestation after long time (in adults) diseases which had been provoked in differentiating cells (e.g. during gestation). This was demonstrated using animal experiments as well, as comparative statistical methods (in human cases). However, there is no explanation for the tools of memorization (even after decades) of the early adversity and the tools of execution (manifestation) in adult age. It seems likely that immune memory is involved to the memorization of early adversity, up to the manifestation of the result (non-communicable diseases). Nevertheless, the relatively short timespan of adaptive immune memory makes this system insuitable for this function, however the newly recognized trained memory of the innate immune system seems to be theoretically suitable for the storage of the records and handling the sequalae, which is the epigenetic reprogramming in the time of provocation, without changes in base sequences (mutation). The flawed (damaged) program is manifested later, in adult age. Evidences are incomplete, so further animal experiments and human observations are needed for justifying the theory.

Hormonal Imprinting: The First Cellular-level Evidence of Epigenetic Inheritance and its Present State.

Hormonal imprinting takes place perinatally at the first encounter between the developing hormone receptor and its target hormone. This process is needed for the normal function of the receptor-hormone pair and its effect is life-long. However, in this critical period, when the developmental window is open, related molecules (members of the same hormone family, synthetic hormones and hormone-like molecules, endocrine disruptors) also can be bound by the receptor, causing life-long faulty imprinting. In this case, the receptors' binding capacity changes and alterations are caused at adult age in the sexual and behavioral sphere, in the brain and bones, inclination to diseases and manifestation of diseases, etc. Hereby, faulty hormonal imprinting is the basis of metabolic and immunological imprinting as well as the developmental origin of health and disease (DOHaD). Although the perinatal period is the most critical for faulty imprinting, there are other critical periods as weaning and adolescence, when the original imprinting can be modified or new imprintings develop. Hormonal imprinting is an epigenetic process, without changing the base sequence of DNA, it is inherited in the cell line of the imprinted cells and also transgenerationally (up to 1000 generations in unicellulars and up to the 3rd generation in mammals are justified). Considering the enormously growing number and amount of faulty imprinters (endocrine disruptors) and the hereditary character of faulty imprinting, this latter is threatening the whole human endocrine system.

Immunity and longevity.

The role of immune system is to protect the organism from the not built-in program-like alterations inside and against the agents penetrating from outside (bacteria, viruses, and protozoa). These functions were developed and formed during the evolution. Considering these functions, the immune system promotes the lengthening of lifespan and helps longevity. However, some immune functions have been conveyed by men to medical tools (e.g., pharmaceuticals, antibiotics, and prevention), especially in our modern age, which help the struggle against microbes, but evolutionarily weaken the immune system. Aging is a gradual slow attrition by autoimmunity, directed by the thymus and regulated by the central nervous system and pineal gland. Considering this, thymus could be a pacemaker of aging. The remodeling of the immune system, which can be observed in elderly people and centenarians, is probably not a cause of aging, but a consequence of it, which helps to suit immunity to the requirements. Oxidative stress also helps the attrition of the immune cells and antioxidants help to prolong lifespan. There are gender differences in the aging of the immune system as well as in the longevity. There is an advantage for women in both cases. This can be explained by hormonal differences (estrogens positively influences both processes); however, social factors are also not excluded. The endocrine disruptor chemicals act similar to estrogens, like stimulating or suppressing immunity and provoking autoimmunity; however, their role in longevity is controversial. There are some drugs (rapamycin, metformin, and selegiline) and antioxidants (as vitamins C and E) that prolong lifespan and also improve immunity. It is difficult to declare that longevity is exclusively dependent on the state of the immune system; however, there is a parallelism between the state of immune system and lifespan. It seems likely that there is not a real decline of immunity during aging, but there is a remodeling of the system according to the claims of senescence. This is manifested in the remaining (sometimes stronger) function of memory cells in contrast to the production and number of the new antigen-reactive naive T-cells.

Hormesis and immunity: A review.

The hormesis concept demonstrates that in contrast to the toxic effect of high doses of materials, irradiation, etc., low doses of them are beneficial and, in addition, help to eliminate (prevent) the deleterious effect of high doses given after it. By this effect, it is an important factor of (human) evolution protecting man from harmful impacts, similarly to the role of immunity. However, immunity is also continuously influenced by hormetic effects of environmental [chemical (pollutions), physical (background irradiations and heat), etc.] and medical (drugs and therapeutic irradiations) and food interactions. In contrast to earlier beliefs, the no-threshold irradiation dogma is not valid in low-dose domains and here the hormesis concept is valid. Low-dose therapeutic irradiation, as well as background irradiations (by radon spas or moderately far from the epicenter of atomic bomb or nuclear facilities), is rather beneficial than destructive and the fear from them seems to be unreasonable from immunological point of view. Practically, all immune parameters are beneficially influenced by all forms of low-dose radiations.

[The crisis of the hormonal system: the health-effects of endocrine disruptors]. / A hormonális rendszer válsága: az endokrin diszruptorok egészségügyi hatásai.

The endocrine disruptors are natural or arteficial molecules wich are present in the animal (human) environment and entering into the organism. They are bound by hormone receptors, simulating or inhibiting the normal hormonal message. This way they are able to stimulate or hinder the function of the given cell, as well as the synthesis and transport of hormones or receptors. They can cause faulty hormonal imprinting in critical periods of development with lifelong consequences, as alteration of hormone-influenced cell functions, inclination to or manifestation of diseases, so they have medical importance. The number of endocrine disruptors as well as their amount are large and continously growing. Numerous, in adult age manifested disease (e.g. malignant tumors) can be deduced to perinatal harms. Their long-lasting effect can cause the alteration of basal human developmental characteristics (e.g. start of menarche). Vitamins A and D are hormones (exohormones) and could be endocrine disruptors. Perinatal imprinting caused by endocrine disruptors is transmitted to the progenies epigenetically, which also can influence the drug-sensitivity of offspring' receptors. If the epigenetic change is continuously transmitted to the progeny generations, this could have human-evolutionary importance. Orv Hetil. 2017; 158(37): 1443-1451.

[Revaluation of the concept of developmental abnormality: the importance of faulty perinatal imprinting]. / A fejlodési rendellenesség fogalmának átértelmezése: a hibás perinatalis imprinting jelentosége.

The classic definition of developmental abnormalities referred to malformations observed at birth. Later the functional teratogenicity was also recognized and accepted, which can be revealed in functional abnormalities caused by harms during the intrauterine development and can be manifested at any time of life. However, the ontogeny is not closed with the birth, because some systems or organs are developing for a long time after it, and can be influenced by different factors. From this aspect the perinatal period is especially important when the mutual adjustment of the receptor-hormone system is taking place and the hormonal imprinting develops. If this is faulty, it influences the hormone binding capacity of receptors that has consequences for life. The faulty hormonal imprinting is functionally teratogen; it provokes a fault up to the level of a malformation and aggravated with its heredity to the progenies. False imprinting is provoked (in animal experiments, proportioning to human doses) by drugs acting at receptor level, as oxytocin, steroid hormone analogues (pregnancy protectors, oral contraceptives, surfactants), vitamin A and D, environmental pollutant endocrine disruptors (benzpyrene, bisphenol A, pesticides, herbicides) and certain soybean components, etc. From this aspect these are functional teratogens, and their evasion in prevention as well as therapy seems to be vital. This means that the concept of developmental abnormality must be broadened, as developmental abnormalities: 1.) can originate not only in the intrauterine period, but also perinatally or even later, 2.) it can be manifested at any time of life, 3.) it can be present in a latent form which can be activated by inner or outer environmental factors, 4.) the faulty hormonal imprinting is a teratogen factor.

[Late manifested sequelae of medications in the critical periods of development. The widening of the faulty hormonal imprinting conception]. / Az egyedfejlodés kritikus fázisaiban történo gyógyszeres kezelések késoi következményei. A hibás hormonális imprinting koncepciójának kiterjesztése.

Hormonal imprinting is a physiological process, which is a part of the receptor-hormone complex development. It determines the binding capacity of the receptors across the lifespan. It takes place perinatally in the critical period of hormone receptor development, when the developmental window for imprinting is open and permits the binding of hormone-like molecules (related or synthetic hormones, endocrine disruptors etc.) causing disturbances of the endocrine system, and the systems- influenced organs by it, for life. This is the faulty hormonal imprinting. However, studying the medical database, PubMed, a lot of data can be found on the harmful late (adult age) effects of medication in the critical period of development with non-hormonal molecules, which are manifested later in functional alterations or diseases. This could mean that in the process of faulty imprinting, the openness of the developmental window could be more important than the structural similarity of a molecule to hormones. As developmentally critical period for faulty imprinting by hormone-like molecules is not exclusively the perinatal one (this is justified in the case of faulty hormonal imprinting), the pubertal period was also studied from this aspect and similarities to the impact of perinatal use have been found (this could be called "Pubertal Origin of Health and Disease = POHaD). While in the case of hormonal faulty imprinting, the mechanism seems to be clear (considering the role of receptors), the mechanism of drug-provoked imprinting is presently uncleared (considering the variety of medications which cause late-manifested alterations). The medicaments-caused faulty imprinting conception calls attention to the dangers of medication in the perinatal as well as the pubertal periods. Orv Hetil. 2020; 161(2): 43-49.

Programming and reprogramming from conception till death / Programozás és átprogramozás fogamzástól mindhalálig

During conception (fusion of maternal and paternal germ cells) a new entity is formed, which has individual structure and functions. From its gene-pool (genome) epigenetic regulation selects those genes which are durably or acutely working, supplying a theoretically lifelong program. However, this program could be changed spontaneously or artificially, and there are life periods when the spontaneous changes are especially frequent and the sensitivity to physiological or artificial (man-made) factors is high. The basic sensitive (most vulnerable) period is the perinatal one, when the program agglomerated (and this is manifested in the faulty hormonal imprinting and DOHaD theories: perinatal adverse effects can cause diseases in adults), however, later periods are also sensitive. Such rather sensitive periods are the puberty and periadolescence as well as weaning, nevertheless, in any periods of life, cells or cell groups could be epigenetically imprinted, if the cells are in the state of differentiation, independent of the age or developmental state of the complete organism. Earlier mainly natural molecules (products of volcanic eruptions or phytoestrogens, mykotoxins, tobacco) threatened the program, today man-made artificial molecules (endocrine disruptors) can reprogram the visibly stable program, by a single encounter with hormone receptors at the periods of sensitivity (faulty hormonal imprinting) with life-long consequences (altered cell functions, inclination to diseases, manifestation of diseases, etc., provoked by functional teratogens). The deformed program is inherited to the offspring generations, where further program transformations are taking place on the inherited (transformed) program. As the amount and variants of man-made endocrine disruptors are enormously growing in the human environment and its important parts act during the developmentally most sensitive periods, the diseases provoked by them in adults expectedly will be enormously accruing. Orv Hetil. 2020; 161(25): 1028-1034.

DOHaD: a disease-oriented, epoch-making, British-originated theory with Hungarian roots / [DOHaD (Barker-hipotézis): egy betegségorientált, korszakalkotó, brit eredetu teória, magyar gyökerekkel]

On the basis of comparative epidemiological statistical studies, the 'developmental origin of health and disease' (DOHaD) theory was published in 1986, testifying the interrelation between certain perinatal events, like under- and overfeeding as well as infant mortality with cardiovascular lethality in adults (Barker DJ, Osmond C, Lancet, 1986; 137: 1077­1081) ­ and at present it is widely extended. The theory is rather similar to the hormonal imprinting concept, which had been published 6 years earlier (Csaba G, Biol Rev Cambr Philos Soc. 1980; 55: 47­63 and Horm Metab Res. 1984; 16: 329­335). This demonstrated the role of perinatal encounter with hormones or hormone-like molecules with adult's endocrino-pathological events based on animal experiments. Barker hypothesized the role of hormonal imprinting in DOHaD (Phillips DI, Barker DJ, Osmond C, Acta Endocrinol (Copenh). 1993; 129: 134­138: "A possible explanation is that thyroid hormones present in the breast milk and absorbed by the suckling infant could, by the process of hormonal imprinting, permanently down-regulate the set point of thyroid homeostasis", and this could have encouraged him to create the theory. Both theories suggest the relationship between the perinatal events and adult-age disease manifestation, however, in the case of faulty imprinting, perinatal disease does not have a role in the provocation by imprinters (only the encounter between the imprinter and the hormone receptor), but in the case of DOHaD, this seems to be involved in the process. The whole process points to the disturbance of epigenetic programming. On the basis of the present standpoint, DOHaD is valid in non-communicative diseases, however, considering the impact of faulty hormonal imprinting to the immune system, the extension to communicative diseases is expected and likely also the involvement of lifespan. Further critical developmental period is the adolescence (puberty), when similar reprogramming could be possible and also in certain cases (e.g., in the immune system) disease-causing reprogramming could occur during the whole life. The two concepts are not racing, but using different methods for verification supplement and support each other, by building up identical conclusions (faulty reprogramming) giving epigenetical explanation for numerous diseases. DOHaD and its antecedent, hormonal imprinting are not only theories, but realities, which are commendable to consider in diagnosis and therapy. Studying the tendencies of human creativeness, in all probability, the importance of DOHaD (and faulty imprinting) will be growing in the near and far future. Orv Hetil. 2020; 161(16): 603­609.

Bone Manifestation of Faulty Perinatal Hormonal Imprinting: A Review.

Hormonal imprinting takes place at the first encounter between the developing receptor and its target hormone and the encounter determines the receptor's binding capacity for life. In the critical period of development, when the window for imprinting is open, the receptor can be misdirected by related hormones, synthetic hormones, and industrial or communal endocrine disruptors which cause faulty hormonal imprinting with life-long consequences. Considering these facts, the hormonal imprinting is a functional teratogen provoking alterations in the perinatal (early postnatal) period. One single encounter with a low dose of the imprinter in the critical developmental period is enough for the formation of faulty imprinting, which is manifested later, in adult age. This has been justified in the immune system, in sexuality, in animal behavior and brain neurotransmitters etc. by animal experiments and human observations. This review points to the faulty hormonal imprinting in the case of bones (skeleton), by single or repeated treatments. The imprinting is an epigenetic alteration which is inherited to the progeny generations. From clinical aspect, the faulty imprinting can have a role in the pathological development of the bones as well, as in the risk of osteoporotic fractures, etc.

Effect of endocrine disruptor phytoestrogens on the immune system: Present and future.

Endocrine disruptors (EDs) are bound by steroid receptors, have steroid-like effects, and by this, negatively influence hormone-regulated processes. Phytoestrogens, which are consumed in enormously high amount by man, are also EDs; however, in contrast to industrial or communal EDs, in some cases have beneficial effects. As immune cells have steroid (first of all, estrogen) nuclear and plasma membrane receptors, which bind phytostrogens (genistein, daidzein, etc.), the development, lifespan, and function of them are deeply influenced by phytoestrogens. They can provoke perinatal faulty hormonal imprinting with lifelong consequences. However, faulty imprinting can be developed not only perinatally but also in other critical periods of life, as weaning, adolescence, and even in continuously dividing cells (e.g., hemopoietic cells) during the whole life. This means that the phytoestrogens could cause direct - instant or long-lasting - steroid effects and durable imprinting effects. As the effect of hormonal imprinting is epigenetically inherited, the phytoestrogen's effects appear in the progeny generations, and the generationally repeated disruptor effects will be different from the present ones. This could also be manifested in the amount, type, and appearance of autoimmune diseases. The consumption of soy is enormously growing, and its immune effect is extended. As the immune system influences basic physiological processes, it seems likely that evolutionary alterations will be observed. In this case, some phytoestrogens will be needed for the normal life of man, as it happened in the case of vitamins A and D, which are already life-important exohormones. However, quantitatively or qualitatively enormous amount of phytoestrogens will cause pathological and epigenetically inherited alterations.

Complex multicellular functions at a unicellular eukaryote level: Learning, memory, and immunity.

According to experimental data, eukaryote unicellulars are able to learn, have immunity and memory. Learning is carried out in a very primitive form, and the memory is not neural but an epigenetic one. However, this epigenetic memory, which is well justified by the presence and manifestation of hormonal imprinting, is strong and permanent in the life of cell and also in its progenies. This memory is epigenetically executed by the alteration and fixation of methylation pattern of genes without changes in base sequences. The immunity of unicellulars is based on self/non-self discrimination, which leads to the destruction of non-self invaders and utilization of them as nourishment (by phagocytosis). The tools of learning, memory, and immunity of unicellulars are uniformly found in plasma membrane receptors, which formed under the effect of dynamic receptor pattern generation, suggested by Koch et al., and this is the basis of hormonal imprinting, by which the encounter between a chemical substance and the cell is specifically memorized. The receptors and imprinting are also used in the later steps of evolution up to mammals (including man) in each mentioned functions. This means that learning, memory, and immunity can be deduced to a unicellular eukaryote level.

The Present and Future of Human Sexuality: Impact of Faulty Perinatal Hormonal Imprinting.

INTRODUCTION: Hormonal imprinting occurs perinatally, when the developing hormone receptors connect to their target hormones. This is required for the normal development of the receptor-hormone connection. At this time, the selectivity of receptors is weak and can be misdirected to related endogenous or exogenous molecules, such as other members of the same hormone family, synthetic hormones, drugs, hormone-like environmental pollutants, and endocrine disruptors. In this situation, faulty hormonal imprinting develops with lifelong consequences, which are manifested by altered receptor binding capacity, hormone production, changed bone formation, and brain neurotransmitter content. The effect of faulty imprinting is epigenetically inherited and manifested in progeny. AIM: To evaluate the effects of hormonal imprinting on sexuality based on published results. METHODS: Review of perinatal (mainly single) treatment of experimental animals with hormones or hormone-like materials and the study of their effects in adulthood and in progeny. MAIN OUTCOME MEASURE: Consistency of experimental results with the previous information and expectations. RESULTS: In each published experiment, perinatal treatments with hormones acting on members of a steroid receptor superfamily or endocrine disruptors (eg, bisphenol A, vinclozolin, benzpyrene or soybean genistein) caused faulty imprinting with altered sexual hormone receptor binding and sexual function. Indices of sexual activity showed the strong influence of these treatments. CONCLUSION: Sexuality is influenced by perinatal faulty hormonal imprinting at the receptor and behavioral levels. Because faulty imprinting is an epigenetic process, it is transmitted to the members of cell line and to progeny. In the modern age, the amount of artificial (industrial, communal, and medical) imprinters and their effects on the human organism are increasing enormously. This is likely to change human sexuality now and in the future. Csaba G. The Present and Future of Human Sexuality: Impact of Faulty Perinatal Hormonal Imprinting. Sex Med Rev 2017;5:163-169.

Vitamin-caused faulty perinatal hormonal imprinting and its consequences in adult age.

Lipid-soluble vitamins (vitamins A, D, E, and K) are actually hormones (exohormones), as they can be directly bound by hormone receptors or are in connection with molecules, which influence hormone receptors. Vitamin D is a transition between endo- and exohormones and the possibility of similar situation in case of other lipid-soluble hormones is discussed. The perinatal exposition with these "vitamins" can cause faulty perinatal hormonal imprinting with similar consequences as the faulty imprinting by the synthetic endohormones, members of the same hormone family or industrial, communal, or medical endocrine disruptors. The faulty imprinting leads to late (lifelong) consequences with altered hormone binding by receptors, altered sexuality, brain function, immunity, bone development, and fractures, etc. In addition, as hormonal imprinting is an epigenetic process, the effect of a single exposure by fat-soluble vitamins is inherited to the progeny generations. As vitamins are handled differently from hormones; however, perinatal treatments take place frequently and sometimes it is forced, the negative late effect of faulty perinatal vitamin-caused hormonal imprinting must be considered.

Immunoendocrinology: faulty hormonal imprinting in the immune system.

Hormonal imprinting is an epigenetic process which is taking place perinatally at the first encounter between the developing hormone receptors and their target hormones. The hormonal imprinting influences the binding capacity of receptors, the hormone synthesis of the cells, and other hormonally regulated functions, as sexual behavior, aggressivity, empathy, etc. However, during the critical period, when the window for imprinting is open, molecules similar to the physiological imprinters as synthetic hormone analogs, other members of the hormone families, environmental pollutants, etc. can cause faulty imprinting with life-long consequences. The developing immune system, the cells of which also have receptors for hormones, is very sensitive to faulty imprinting, which causes alterations in the antibody and cytokine production, in the ratio of immune cells, in the defense against bacterial and viral infections as well as against malignant tumors. Immune cells (lymphocytes, monocytes, granulocytes and mast cells) are also producing hormones which are secreted into the blood circulation as well as are transported locally (packed transport). This process is also disturbed by faulty imprinting. As immune cells are differentiating during the whole life, faulty imprinting could develop any time, however, the most decisive is the perinatal imprinting. The faulty imprinting is inherited to the progenies in general and especially in the case of immune system. In our modern world the number and amount of artificial imprinters (e.g. endocrine disruptors and drugs) are enormously increasing. The effects of the faulty imprinters most dangerous to the immune system are shown in the paper. The present and future consequences of the flood of faulty imprintings are unpredictable however, it is discussed.

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.