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.

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.

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.

Environmental Pollution and Non-Perinatal Faulty Hormonal Imprinting: A Critical Review

The perinatal hormonal imprinting takes place perinatally, when the developing hormone receptors meet the hormones of the newborn and this suits the normal receptor-hormone connections for life. In this period the developmental window for imprinting is open and the receptors can be cheated by hormone-related exogeneous molecules, provoking faulty hormonal imprinting with lifelong consequences, as alteration of receptor binding capacity and hormone production, functional changes, altered sexual behavior, immunological alterations and inclination to or manifestation of diseases. However, there are other critical periods of life, when the window is open, as weaning, adolescence, regeneration in adults as well, as in continously dividing cells. The most sensitive non-perinatal critical period is the adolescence. In these periods hormone-like endocrine disruptors (e.g. bisphenol A, benzpyrene, pesticides and herbicides, soy isoflavones, medically used synthetic hormones etc) are provoking faulty hormonal imprinting with lifelong consequences. The hormonal imprinting is an epigenetic process, which is inherited to the progeny cells of the organism and to the offspring of the organism, by which it can chip in the evolution. The non-perinatal faulty hormonal imprinting is justified in animal experiments and seems to be likely in case of survivors of childhood cancer treatment. Similar to the faulty perinatal hormonal imprinting, the late (non-perinatal) faulty imprinting can participate in the provocation of later manifested diseases.

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.