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.

in biology by Douglas Spalding in the late XIX century however, it is expanded by the publications of Konrad Lorenz, especially when the author won the Nobel-prize in 1973. This was a behavioural imprinting, when the goslings accepted a moving subject as the mother in the early postnatal stage of their life. This inspired us to name the fitting of developing receptors to the neonatal hormones "hormonal imprinting" in 1980 [5]. After that, other imprinting names appeared as genomic imprinting [6], metabolic imprinting [7] and epigenetic imprinting [8].
The fetus develops in the maternal womb and is influenced by maternal hormones which are passing across the placental blood wessels. Nearing the labour it is the time to hand over the governing to the endocrine system from the mother to the fetus itself, and after birth the complete guidance is done by this latter. These requests the hormonal imprinting when the developing receptor recognizes the hormones of the newborn and bind them, developing a connection which -in normal cases-will be valid in the whole life [9]. However, for the change-over from the maternal hormones to the hormones of its own requests an open developmental window during which the specificity of receptors are not complete, consequently there is a possibility of imprinting by related molecules [10][11][12]. These could be hormones of the same hormone family, synthetic hormones, drugs, hormone-like molecules of environmental pollution (endocrine disruptors) etc. Imprinting by these or similar molecules cause faulty hormonal imprinting with life-long consequences, as change in receptor binding capacity, alteration of hormone production, immunity, sexual behavioural abnormalities, inclination to or manifestation of diseases, etc [13][14][15][16]. As the faulty imprinting causes epigenetic changes, these are inherited also to the progeny generations [17-21].

The Facts
Faulty hormonal imprinting during weaning Weaned (25 day old) female rats were treated with endorphin, and endorphin and serotonin content were measured in adults. Peritoneal lymphocytes and blood monocytes contained less endorphin and peritoneal mast cells less serotonin [22]. After single endorphin treatment of three-week old female rats serotonin content in five regions of the brain, sexual activity, uterine estrogen receptor binding were measured in adults. Brain serotonin levels and uterine estrogen receptor affinity decreased, and sexual activity increased [23]. Three weeks after single treatment with benzpyrene or H1 receptor blocker antihistamine, chlorpheniramine of weanling rats, serotonin content of white blood cells and mast cells were strongly influenced [24]. Two weeks after 3-day antihistamine (terfenadine) treatment at weaning the histamine content of blood lymphocytes and glucocorticoid receptor density of liver cells were decreased [25]. Weanling female rats were treated and the effects were maeasured at adult age. The histamine and serotonin blocker mianserin increased glucocorticoid receptor density and decreased affinity. Vitamin D3 and benzpyrene increased receptor density [26]. Mianserin treatment was done at weaning and brain serotonin and cerebrospinal fluid nocistatin was measured when adult: brain serotonin decreased in four loci and nocistatin strongly elevated [27]. H1 receptor blocker antihistamine, terfenedine was used for provoking imprinting in weanling rats. Weanling female rats were stressed by water and food deprivation for two days and 5-HIAA content of hypothalamus and brainstem decreased and in the striatum increased, when adults. The estrus frequency almost doubled in the weanling-stressed animals [28]. The synthetic steroid hormone, allylestranol which is a strong imprinter up to the 3 rd day after birth in rat, losts its imprinter effect between the 4 th and 8 th days [29].
After cortisol treatment or stress during the first 9 or 16 days of life, in the adult rats an increase of tyrosine aminotransferase activity was observed [30]. Emotional stress during milk feeding caused a change in the concentration of sex hormones and protein and lipid metabolism of adult rats [31]. Leptin treatment during the first 10 days of lactation caused elevated adrenal catecholamine content and tyrosine hydroxylase expression in adult age [32].

Faulty hormonal imprinting during adolescence
Retinol (vitamin A) or retinoic acid treatment of 6 or 7 weeks old male and female rats significantly influenced steroid hormone levels of the adult age [33]. Retinol decreased testosterone level, without influencing progesterone level, while retinoic acid also decreased testosterone and increased progesterone level. Single vitamin D3 treatment of six weeks old male rat increased the thymic glucocorticoid receptor density of adult males [34]. The density of uterine estrogen receptors and thymic glucocorticoid receptors of adult female rats decreased after single adolescent treatment with the anabolic steroid nandrolone [35]. In male rats digoxin treatment at puberty increased the libido (number of intromissions) of adults and reduced the number of ejaculations [36].
The aromatic hydrocarbon (environmental pollutant) benzpyrene exposition in adolescence of male rats caused a total failure of male's ejaculation [37] and a durable decrease of female's estrogen receptor density. The imprinting was transgenerationally transmitted, as the uterine estrogen receptors' density was higher in the offspring than that of the controls [38]. Eight weeks old rats were treated with serotonin and a radical reduction of serotonin content of male's white blood cells (lymphocytes, monocytes, granulocytes) and mast cells were observed in adult age [39]. Seven weeks old rats were treated with gonadotropin and the thyroidic response to TSH decreased in adult age [40]. Tamoxifen treatment during adolescence dramatically reduced the sexual activity of femal and male rats four to six weeks after treatment [41].
Prostatic hyperplasia developed in adult rats, which had a growth hormone excess between the 45-59 days of life [42]. In Mongolian gerbils pubertal testosterone exposure induced a broad effect on prostate development and increased the susceptability to prostate diseases [43]. A dramatic rewiring of the nervous system was observed by steroid hormone (testosterone) treatments during adolescence of male Syrian hamsters [44] [45], which deeply infuenced the social maturation. In mice chronic social stress during adolescence deeply influenced obesity and visceral fat accumulation in adulthood [46].

Faulty hormonal imprinting in adults
Three weeks after single serotonin treatment of adult rats peritoneal white blood cells and mast cells as well, as white blood cells were studied for serotonin and histamine content [48]. Both amines were higher in mast cells of males and lower in females. Peritoneal cells contained less serotonin in both genders. Thymocytes contained higher levels of both amines in females and higher histamine level in males. Single treatment with the H1 receptor blocker terfenadine measured after 3 weeks, caused elevation of histamine levels in peritoneal mast cells and decrease in thymic lymphocytes [49]. Insulin treatments of rats during liver regeneration provoked the increase of insulin binding in females and decrease in males 2 weeks after the operation [50] [51]. The treatment with diethylstilbestrol (DES) provoked an elevation of microsomal enzymes in female rats 5 and 7 weeks after treatment and allylestrenol treatment does the same after 7 weeks [52]. Genistein, the isoflavone of soy given to prepubertal and adult periods protected against chemically induced mammary cancer [53].

Conclusion
The facts clearly show that although the perinatal physiological or faulty imprinting has a decisive role on the connection between the receptors and their target hormones, there are other critical periods when this connection could be deeply and durably influenced. This means that the developmental window is not definitively closed after the critical perinatal period, it is opened many times during life and this has physiological importance in some important life-processes. However, at the same time it can be dangerous, as the stable physiological state could be transformed to a pathological one.
It seems to be sure that the developmental window for imprinting does not open for the sake of external stimuli, as this is a physiological part of the never-ending developmental processes inside an organism, which helps to adapt to the continuously changing internal milieu. The requirements of hormonal regulation are not stable during life, as the development does not finished at the time of birth and the importance of certain components are changing. This requests also the reprogramming of receptor-hormone relations. In the case of continuously dividing cells -as it was observed in the case of immune cells-this process is present during the whole life [54]. However, there must be some landmarks, when the whole organism is inclined to be reprogrammed. This is well known in the case of puberty, when the whole brain is involved in the alterations [55] [56], consequently also the brain-regulated organs and cells. In other critical periods, as the weaning or regeneration also there is a higher sensitivity for reprogramming the receptorhormone connection. There is not a period for direct fitting to external molecules which normally are rather avoidable by the organisms however, especially in our modern chemically infected age these molecules cannot be avoidable and entering into the organisms disturb the the process of reprogramming, provoking faulty hormonal imprinting [2] [57].
It seems likely that in earlier centuries were also possibilities of influencing the hormonal system by exogeneous factors. However, the quality and quantity of these possibilities extremely increased. The enormous development of industry and agrotechnics produce and requires such substances which have hormone-like structures and these can enter into the animal and human organisms and can be recognized and bind by hormone receptors, causing faulty hormonal imprinting. These materials are named endocrine disruptors and they are present in the food and water as well, as in the toys [58] and cosmetics [59], and cannot be avoided. For example bisphenol A (BPA), which has an estrogen character is used in plastic factories and causes altered neurobehavior [60]. From BPA -which is presently believed one of the most dangerous-more than 6 billion pounds/year is produced globally and it is present in plastics and solved into their contents [61]. Benzpyrene, which can be bound by androgene receptors, is present in the air and only 7% of the European population is living in areas where its concentration is less, than the acceptable risk level [62]. As experiments demonstrated, this benzpyrene is a strong imprinter which acts in each sensitive period of life [63]. Also endocrine disruptors (and imprinters) are some foods, as soy [64], containing isoflavones, genistein and daidzein. Soy is favorized now in European and American kitchens causing not completely cleared beneficial or harmful effects. Likewise endocrine disruptors are numerous medicaments, preference for today's doctors and also for women, who want to avoid non-wanted pregnancies. In addition the endocrine disruptors -as their imprinting effect is transgenerationally inherited [18] to the progeny generations-could influence the evolution of mankind [65].
It seems to be the most sensitive non-perinatal period for faulty hormonal imprinting the adolescent age. During adolescence the brain is reprogrammed according to the actual state of hormonal system [66], without alterations in the DNA sequences. This is an epigenetic reprogramming by the methylation of DNA cytosins, the histones and the changes of some small RNA-s. This means that not the inherited DNA informations are changed but the expression of genes [66] [67]. This rearrangement is manifested in the labile (chaotic) state of puberty and in the changes which are permanent after the finishment of adolescence. Hormonal imprinting which is an epigenetic process can strongly act in this chaotic period however, if it does happen by endogeneous and endogenously regulated factors it is physiological, and does not cause problems. Nevertheless, exogeneous factors which can cheat the receptors and bound by them, can cause sweeping and life-long changes [68] [69].
The effect of non-perinatal imprinting is widespread, as it is in case of perinatal exposition. This is manifested not only in the broad spectrum of receptorial alterations by a given imprinter, but also in the imprinting of microsomal enzyme system which can be executed neonatally [70], in adolescence [47] [71] or in adult age [52] [72]. This suggests that not only the endocrine system, but other -hitherto did not studied-systems also could be imprintable during the whole life.
The data collected by us (facts) are results of experiments on laboratory animals, as there are not direct human data. So we can only suppose, that the situation is similar in human beings. However, there are observations of pathological situations which permit the conclusion that in men there is also non-perinatal faulty hormonal imprinting. It was observed in case of endocrine outcomes in adult survivors of childhood and adolescent cancer. Very frequent consequences of the successful chemotherapy or radiological treatment with long-lasting survival are some endocrinopathies, independently of the type of treatment or the type of malignancy. The endocrine disturbances are manifested in hypothyroidism, growth hormone deficiency, adrenocorticotropin deficiency, hypoprolactinemia, hypogonadism, diabetes, osteopenia, erectile disfunction and other altered sexual function, precocious puberty, metabolic syndrome and hypothalamic obesity [73][74][75][76][77]. It seems likely that the treatment itself is the reason of consequences, the endocrinopathies, which affects 20-50% of the cancer survivors [78]. Just the independence on the type of malignancy and treatment as well as the age of the treated patient point to the likelihood of faulty imprinting. Chemotherapy as well, as irradiation are stressful events, and chronic stress in animal experiments is able to provoke faulty imprinting in the endocrine system [30][31] at non-perinatal ages [69], and adolescent age is the most vulnerable. The effect of the treatment can be handled as post-traumatic stress disorder which is manifested as a sequel of drastic treatments in rather vulnerable periods [79].
As it was mentioned earlier, in many cases of the diseases manifested in adult age perinatal faulty programming (imprinting) is guessed and the number of such diseases are increasing [80][81][82][83]. Considering the results of experiments on animals and observations of human beings presented in this paper, the role of the aftermath of late (non-perinatal) faulty imprintings also cannot be excluded.

Declaration
There is not conflict of interest.