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Hormones, characteristic to higher ranked animals, are synthesized, stored, and secreted by unicellular eukaryote animals. The unicells also have receptors for recognizing these materials and transmit the message into the cells for provoking response. The hormones are effective in very low concentrations (down to 10–21 M) and opposite effects of lower and higher concentrations can be observed. However, sometimes linear concentration effects can be found, which means that hormesis exists, nevertheless uncertain, as it is in the phase of formation (evolutionary experimentation). Hormesis, by transformation (fixation) of cytoplasmic receptor-like membrane components to receptors in the presence of the given hormone, likely helps the development of unicellular endocrine character and by this the evolution of endocrine system. The effect by extremely low concentrations of hormones had been forced by the watery way of unicellular life, which could establish the physiological concentrations of hormones in the blood of higher ranked animals. This means that hormetic low doses are the normal, effective concentrations and the high concentrations are artificial, consequently could be dangerous.

A perinatalis hormonális imprinting fogalma először 1980-ban jelent meg és azóta széleskörűen elterjedt. Az imprinting a fejlődő receptor és a megfelelő hormon első találkozásakor megy végbe – valószínűleg a DNS metilációs mintázatának megváltozása által –, és hatása a sejtek utódgenerációiban élethossziglan tart. Szükséges a receptor kötési képességének teljes kialakulásához. A fejlődő receptorhoz azonban egyéb – a célhormonhoz hasonló – molekulák (receptorszinten ható hormonanalógok, gyógyszerek, vegyszerek, környezetszennyező anyagok) is kötődni képesek, ugyancsak életre szóló hibás imprintinget hozva létre. Ez kóros állapotokat okozhat. Később kiderült, hogy egyéb kritikus periódusokban, mint a pubertás, szintén imprinting jöhet létre, sőt differenciálódó sejtekben az élet bármely szakaszában. Az imprinting a szülőről az utódra is átadódik, azaz epigenetikusan öröklődik, valószínűleg emberben is. A központi idegrendszer is (hibásan) imprintálódhat, ami a dopaminerg, szerotonerg és noradrenerg rendszert tartósan befolyásolja, így a szexuális és szociális magatartás zavaraiban is megmutatkozik állatkísérletekben. Korunkban a hibás imprinting létrejötte elkerülhetetlen a gyógyszerek, vegyszerek tömege, az ételekben levő hormonszerű anyagok (például szójafitoszteroidok) és a környezetszennyezés miatt. A szerző különösen kiemeli az oxitocinnak, mint imprinternek veszélyességét, mivel igen széles körben alkalmazzák, miközben imprintingje döntően érintheti az érzelmi és szociális szférát és egyes betegségek – mint az autizmus, szkizofrénia és Parkinson-kór – fellépését. A perinatalis imprinterek veszélyessége azért is nő, mert az imprinting átöröklődve befolyásolhatja az emberi evolúciót. Orv. Hetil., 2013, 154, 128–135.

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.

Phagocytosis is an ancient cell function, which is similar at unicellular and multicellular levels. Unicells synthesize, store, and secrete multicellular (mammalian) hormones, which influence their phagocytosis. Amino acid hormones, such as histamine, serotonin, epinephrine, and melatonin stimulate phagocytosis, whereas peptide hormones, such as adrenocorticotropic hormone (ACTH), insulin, opioids, arginine vasopressin, and atrial natriuretic peptide decreased it, independently on their chemical structure or function in multicellulars. Macrophage phagocytosis of multicellulars is also stimulated by amino acid hormones, such as histamine, epinephrine, melatonin, and thyroid hormones, however, the effect of peptide hormones is not uniform: prolactin, insulin, glucagon, somatostatin, and leptin have positive effects, whereas ACTH, human chorionic gonadotropin, opioids, and ghrelin have negative ones. Steroid hormones, such as estrogen, hydrocortisone, and dexamethasone are stimulating macrophage phagocytosis, whereas progesterone, aldosterone, and testosterone are depressing it. Considering the data and observations there is not a specific phagocytosis hormone, or a hormonal regulation of phagocytosis neither unicellular, nor multicellular level, however, hormones having specific functions in multicellulars also influence phagocytosis at both levels universally (in unicellulars) or individually (in macrophages). Nevertheless, the hormonal influence cannot be neglected, as phagocytosis (as a function) is rather sensitive to minute dose of hormones and endocrine disruptors. The hormonal influence of phagocytosis by macrophages can be deduced to the events at unicellular level.

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.

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 malginant 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 arteficial 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.

Immune cells synthesize, store and secrete hormones, which are identical with the hormones of the endocrine glands. These are: the POMC hormones (ACTH, endorphin), the thyroid system hormones (TRH, TSH, T3), growth hormone (GH), prolactin, melatonin, histamine, serotonin, catecholamines, GnRH, LHRH, hCG, renin, VIP, ANG II. This means that the immune cells contain all of the hormones, which were searched at all and they also have receptors for these hormones. From this point of view the immune cells are similar to the unicells (Tetrahymena), so it can be supposed that these cells retained the properties characteristic at a low level of phylogeny while other cells during the evolution accumulated to form endocrine glands. In contrast to the glandular endocrine cells, immune cells are polyproducers and polyreceivers. As they are mobile cells, they are able to transport the stored hormone to different places (packed transport) or attracted by local factors, accumulate in the neighborhood of the target, synthesizing and secreting hormones locally. This is taking place, e.g. in the case of endorphin, where the accumulating immune cells calms pain caused by the inflammation. The targeted packed transport is more economical than the hormone-pouring to the blood circulation of glandular endocrines and the targeting also cares the other receptor-bearing cells timely not needed the effect. Mostly the immune-effects of immune-cell derived hormones were studied (except endorphin), however, it is not exactly cleared, while the system could have scarcely studied important roles in other cases. The evolutionary aspects and the known as well, as possible roles of immune-endocrine system and their hormones are listed and discussed.

The unicellular eukaryote Tetrahymena synthesize, store and secrete biogenic amines (histamine, serotonin, epinephrine, dopamine, melatonin) and also can take up amines from the milieu. It also has (G-protein-coupled) receptors (binding sites) for these amines as well, as second messengers. The factors infuencing the mentioned processes are shown. For certain amines the genes and the coded enzymes are demonstrated. The amines influence phagocytosis, cell division, ciliary regeneration, glucose metabolism and chemotaxis. There are interhormone actions between the amines, and between the amines and other hormones produced by Tetrahymena. The critical review discusses the role of amines in the early stages of evolution and compares this to their functions in mammals. It tries to give answer how and why biogenic amines were selected to hormones, and why new functions formed for them in higher ranked animals, preserving also the ancient ones.

The mast cell is a member of the immune system having a basic role in allergic (anaphylactic) reactions. However, it contains, synthesizes, stores and secretes lots of substances, which initiates other reactions or participates in them. These are in connection with the deterioration of tissue correlation, as malignant tumors, angiogenesis, wound healing, pregnancy and different pathological conditions. In addition — as other members of the immune system — mast cells can synthesize, store and secrete hormones characteristic to the endocrine glands and can transport them to the site of requirement (packed transport), or produce and employ them locally. The effect of mast cells is controversial and frequently dual, stimulatory or inhibitory to the same organ or process. This is likely due to the heterogeneity of the mast cells, in morphology and cell content alike and dependent on the actual condition of the targeted tissue. The cells are transported in an unmatured form by the blood circulation and are exposed to microenvironmental effects, which influence their maturation. Their enrichment around tumors suggested using them as targets for tumor therapy more than fifty years ago (by the author), however, this idea lives its renaissance now. The review discusses the facts and ideas critically.

The thymus develops from an endocrine area of the foregut, and retains the ancient potencies of this region. However, later it is populated by bone marrow originated lymphatic elements and forms a combined organ, which is a central part of the immune system as well as an influential element of the endocrine orchestra. Thymus produces self-hormones (thymulin, thymosin, thymopentin, and thymus humoral factor), which are participating in the regulation of immune cell transformation and selection, and also synthesizes hormones similar to that of the other endocrine glands such as melatonin, neuropeptides, and insulin, which are transported by the immune cells to the sites of requests (packed transport). Thymic (epithelial and immune) cells also have receptors for hormones which regulate them. This combined organ, which is continuously changing from birth to senescence seems to be a pacemaker of life. This function is basically regulated by the selection of self-responsive thymocytes as their complete destruction helps the development (up to puberty) and their gradual release in case of weakened control (after puberty) causes the erosion of cells and intercellular material, named aging. This means that during aging, self-destructive and non-protective immune activities are manifested under the guidance of the involuting thymus, causing the continuous irritation of cells and organs. Possibly the pineal body is the main regulator of the pacemaker, the neonatal removal of which results in atrophy of thymus and wasting disease and its later corrosion causes the insufficiency of thymus. The co-involution of pineal and thymus could determine the aging and the time of death without external intervention; however, external factors can negatively influence both of them.