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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.
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Azars Braesco V , Pascal G : Vitamin A in pregnancy: requirements and safety limits. Am. J. Clin. Nutr. 71, 1325–1333 (2000)
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Azuma K , Horie-Inoue K , Ouchi Y , Inoue S (2011): Chapter 11 – vitamin K as a ligand of steroid and xenobiotic receptor. In: Advances in Medicine and Biology (Vol. 21), ed Berhardt LV, Nova Science Publishers, Hauppauge, pp. 209–216
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Azuma K , Inoue S : Vitamin K function mediated by activation of steroid and xenobiotic receptor. Clin. Calcium 19, 1770–1778 (2009)
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Barker DJ : Sir Richard Doll lecture. Developmental origins of chronic disease. Public Health 126, 185–189 (2012)
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Bernal J : Thyroid hormone receptors in brain development and function. Nat. Clin. Pract. Endocrinol. Metab. 3, 249–259 (2007)
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Berne B , Nilsson M , Vahlquist A : UV irradiation and cutaneous vitamin A: an experimental study in rabbit and human skin. J. Invest. Dermatol. 83, 401–404 (1984)
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Calkins K , Devaska SU : Fetal origins of adult disease. Curr. Probl. Pediatr. Adolesc. Health Care 41, 158–176 (2011)
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Carlberg C : Lipid soluble vitamins in gene regulation. Biofactors 10, 91–97 (1999)
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Charles MA , Delpierre C , Bréant B : [Developmental origin of health and adult diseases (DOHaD): evolution of a concept over three decades]. Med. Sci. (Paris) 32, 15–20 (2016)
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Chytil F : Vitamin A: not for vision only. Br. J. Nutr. 82, 161–162 (1999)
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Comitato R , Nasaretnam K , Leoni G, Ambra R , Canali R , Bolli A , Marino M , Virgili F : A novel mechanism of natural vitamin E tocotrienol activity: involvement of ER-beta signal transduction. Endocrinol. Metab. 297, E427–E437 (2009)
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Csaba G : Phylogeny and ontogeny of hormone receptors: the selection theory of receptor formation and hormonal imprinting. Biol. Rev. Camb. Philos. Soc. 55, 47–63 (1980)
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Csaba G : Phylogeny and ontogeny of chemical signaling: origin and development of hormone receptors. Int. Rev. Cytol. 155, 1–48 (1994)
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Csaba G : Hormonal imprinting: its role during the evolution and development of hormones and receptors. Cell Biol. Int. 24, 407–414 (2000)
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Csaba G : Hormonal imprinting: phylogeny, ontogeny, diseases and possible role in present-day human evolution. Cell Biochem. Funct. 26, 1–10 (2008)
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Csaba G : The biological basis and clinical significance of hormonal imprinting, an epigenetic process. Clin. Epigenet. 2, 187–196 (2011)
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Csaba G : The immuno-endocrine system: hormones, receptors and endocrine function of immune cells. The packed-transport theory. Adv. Neuroimmunol. Biol. 1, 71–85 (2011)
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Csaba G : Hormones in the immune system and their possible role. A critical review. Acta Microbiol. Immunol. Hung. 61, 241–260 (2014)
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Csaba G : Immunoendocrinology: faulty hormonal imprinting in the immune system. Acta Microbiol. Immunol. Hung. 61, 89–106 (2014)
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Csaba G : Faulty perinatal hormonal imprinting caused by exogeneous vitamin D – dangers and problems. Austin J. Nutr. Food Sci. 4, 1075–1080 (2016)
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Csaba G : The faulty perinatal hormonal imprinting as functional teratogen. Curr. Pediatr. Rev. 12, 222–229 (2016)
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Csaba G : The present and future of human sexuality: impact of faulty perinatal hormonal imprinting. Sex. Med. Rev. 5, 163–169 (2017)
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Csaba G , Gaál A : Effect of perinatal vitamin A or retinoic acid treatment (hormonal imprinting) on the sexual behavior of adult rats. Hum. Exp. Toxicol. 16, 193–197 (1997)
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Csaba G , Inczefi-Gonda Á : Neonatal vitamin E treatment induces long term glucocorticoid receptor changes: an unusual hormonal imprinting effect. Life Sci. 63, 101–105 (1998)
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Csaba G , Inczefi-Gonda Á : Direct and transgenerational effect of benzpyrene treatment at adolescent age on the uterine estrogen receptor and thymic glucocorticoid receptor of the adult rat. Acta Physiol. Hung. 86, 29–36 (1999)
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Csaba G , Inczefi-Gonda Á : Effect of single neonatal vitamin K1 treatment (imprinting) on the binding capacity of thymic glucocorticoid and uterine estrogen receptors of adolescent and adult rats. Life Sci. 65, PL1–PL5 (1999)
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Csaba G , Inczefi-Gonda Á : Effect of vitamin D(3) treatment in the neonatal or adolescent age (hormonal imprinting) on the thymic glucocorticoid receptor of the adult male rat. Horm. Res. 51, 280–283 (1999)
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Csaba G , Inczefi-Gonda Á : Similarities and dissimilarities of newborn and adolescent rats in the binding capacity of thymic glucocorticoid receptors. Mech. Ageing Dev. 122, 327–334 (2001)
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Csaba G , Inczefi-Gonda Á : Molecules acting on receptor level at weaning, durably influence liver glucocorticoid receptors. Acta Physiol. Hung. 92, 33–38 (2005)
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Csaba G , Karabélyos C : Influence of a single treatment with vitamin E or K (hormonal imprinting) of neonatal rats on the sexual behavior of adults. Acta Physiol. Hung. 87, 25–30 (2000)
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Csaba G , Kovács P , Pállinger É : Impact of neonatal imprinting with vitamin A or D on the hormone content of rat immune cells. Cell Biochem. Funct. 25, 717–721 (2007)
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Csaba G , Tekes K : Is the brain hormonally imprintable? Brain Dev. 27, 465–471 (2005)
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Dörner G : Environment- and gene-dependent human ontogenesis, sociogenesis and phylogenesis (eco-geno-onto-socio-phylogenesis). Neuro Endocrinol. Lett. 25, 164–168 (2004)
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Fetahu IS , Höbaus J , Kállay E : Vitamin D and the epigenome. Eur. J. Physiol. 5, 164 (2014)
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Frye CS , Bo E , Calamandrei G , Calza L , Dessi-Fulgheri F , Fernandez M , Fusani L , Kah O , Kajta M , Le Page Y , Patisaul HB , Venerosi A , Wojtowicz AK , Panzica GC : Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. J. Neuroendocrinol. 24, 144–159 (2012)
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Fudvoye J , Bourguignon JP , Parent AS : Endocrine-disrupting chemicals and human growth and maturation: a focus on early critical windows of exposure. Vitam. Horm. 94, 1–25 (2014)
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Gaál A , Bocsi J , Falus A , Szende B , Csaba G : Increased apoptosis of adult rat lymphocytes after single neonatal vitamin A treatment (hormonal imprinting). A flow cytometric analysis. Life Sci. 61, PL339–PL342 (1997)
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Gaál A , Csaba G : Effect of retinoid (vitamin A or retinoic acid) treatment (hormonal imprinting) through breastmilk on the glucocorticoid receptor and estrogen receptor binding capacity of the adult rat offspring. Hum. Exp. Toxicol. 17, 560–563 (1998)
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Gaál A , Csaba G : Testosterone and progesterone level alterations in the adult rat after retinoid (retinol or retinoic acid) treatment (imprinting) in neonatal or adolescent age. Horm. Metab. Res. 30, 487–489 (1998)
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Genuis SJ : Maternal and pediatric health outcomes in relation to gestational vitamin D sufficiency. Obstet. Gynecol. Int. 2015, 501829 (2015)
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Greves NJ , McGrath JJ : Vitamin D as a neurosteroid affecting the developing and adult brain. Annu. Rev. Nutr. 34, 117–141 (2014)
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Hashemi F , Tekes K , Laufer R , Szegi P , Tóthfalusi L , Csaba G : 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? Reprod. Sci. 20, 1255–1263 (2013)
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Hocher B : More than genes: the advanced fetal programming hypothesis. J. Reprod. Immunol. 104–105, 8–11 (2014)
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Horie-Inoue K , Inoue S : Steroid and xenobiotic receptor mediates a novel vitamin K2 signaling pathway in osteoblastic cells. J. Bone Miner. Metab. 26, 9–12 (2008)
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Hypponen E , Laara E , Reunanen A , Jarvelin MR , Virtanen SM : Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 1500–1503 (2001)
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Igarashi M , Yogiahi Y , Mihara M , Takada I : Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene. Mol. Cell. Biol. 27, 7947–7954 (2007)
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Inczefi-Gonda Á , Csaba G , Dobozy O : Effect of a single neonatal treatment with steroid hormone or steroid-like molecules on myocardial ouabain binding in the adult rat. Gen. Physiol. Biophys. 6, 279–283 (1987)
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James SR , Franklyn JA , Kilby MD : Placental transport of thyroid hormone. Best Pract. Res. Clin. Endocrinol. Metab. 21, 253–264 (2007)
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Karabélyos C , Horváth C , Holló I , Csaba G : Effect of neonatal glucocorticoid treatment on bone mineralization of adult nontreated, dexamethasone-treated or vitamin D3-treated rats. Gen. Pharmacol. 31, 789–791 (1998)
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Karabélyos C , Horváth C , Holló I , Csaba G : Effect of neonatal vitamin D3 treatment (hormonal imprinting) on the bone mineralization of adult non-treated and dexamethasone treated rats. Hum. Exp. Toxicol. 17, 424–429 (1998)
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Kidd PM : Vitamins D and K as pleiotropic nutrients: clinical importance to the skeletal and cardiovascular systems and preliminary evidence for synergy. Altern. Med. Rev. 15, 199–204 (2010)
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King MW (2014): Integrative Medical Biochemistry. McGraw-Hill, New York
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Kliewer SA : The nuclear pregnane X receptor regulates xenobiotic detoxification. J. Nutr. 133, 2444S–2447S (2003)
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Kliewer SA , Goodwin B , Willson TM : The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr. Rev. 23, 687–702 (2002)
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Kőhidai L , Lajkó E , Pállinger É , Csaba G : Verification of epigenetic inheritance in a unicellular model system: multigenerational effects of hormonal imprinting. Cell Biol. Int. 36, 951–959 (2012)
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Landes N , Pfluger P , Kluth D , Birringer M , Rühl R , Böl GF , Glatt H , Brigelius-Flohé R : Vitamin E activates gene expression via the pregnane X receptor. Biochem. Pharmacol. 15, 269–273 (2003)
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Mirzahosseini S , Karabélyos C , Dobozy O , Csaba G : Changes in sexual behavior of adult male and female rats neonatally treated with vitamin D3. Hum. Exp. Toxicol. 15, 573–576 (1996)
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Moon JY , Gwak HS : Role of the nuclear pregnane X receptor in drug metabolism and the clinical response. Recept. Clin. Invest. 2, e.996 (2015)
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Morreale de Escobar G , Obregon MJ , Escobar del Rey E : Role of thyroid hormone during early brain development. Eur. J. Endocrinol. 151(Suppl. 3), U25–U37 (2004)
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Morris-Kay GM , Ward SJ : Retinoids and mammalian development. Int. Rev. Cytol. 188, 73–131 (1999)
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Nucera C , Muzzi P , Tiveron C , Farsetti A , La Regina F , Foglio B , Shih SC , Moretti F , Della Pietra R , Mancini F , Sacchi A , Trimarchi F , Vercelli A , Pontecorvi A : Maternal thyroid hormones are transcriptionally active during embryo-foetal development: results from a novel transgenic mouse model. J. Cell. Mol. Med. 14, 2417–2435 (2010)
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Palanza P , Nagel SC , Parmigiani S , Vom Saal FS : Perinatal exposure to endocrine disruptors: sex, timing and behavioral endpoints. Curr. Opin. Behav. Sci. 7, 69–75 (2016)
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Patel J , Landers K , Li H , Mortimer RH , Richard K : Delivery of maternal thyroid hormones to the fetus. Trends Endocrinol. Metab. 22, 164–170 (2011)
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Pembrey M , Saffery R , Bygren LO : Human transgenerational responses to early-life experience: potential impact on development, health and biomedical research. J. Med. Gen. 51, 563–572 (2014)
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Pembrey ME : Time to take epigenetic inheritance seriously. Eur. J. Hum. Gen. 10, 669–671 (2002)
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Penniston KL , Tanumihardjo SA : The acute and chronic toxic effects of vitamin A. Am. J. Clin. Nutr. 83, 191–201 (2006)
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Reichetzeder C , Dwi Putra SE , Hocher B : Developmental origins of disease – crisis precipitates change. Cell. Physiol. Biochem. 39, 919–938 (2016)
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Reichrath J , Lehman B , Carlberg C , Varani J , Zouboulis CC : Vitamins as hormones. Horm. Metab. Res. 39, 71–84 (2007)
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Saurat JH : Skin, sun, and vitamin A: from aging to cancer. J. Dermatol. 28, 595–598 (2001)
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Schnorr CE , Morrone Mda S , Weber MH , Lorenz R , Behr GA , Moreira JC : The effects of vitamin A supplementation to rats during gestation and lactation upon redox parameters: increased oxidative stress and redox modulation in mothers and their offspring. Food Chem. Toxicol. 49, 2645–2654 (2011)
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Sorg O , Tran C , Saurat JH : Cutaneous vitamins A and E in the context of ultraviolet- or chemically-induced oxidative stress. Skin Pharmacol. Appl. Skin Physiol. 14, 363–372 (2001)
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Tekes K , Gyenge M , Folyovich A , Csaba G : Influence of neonatal vitamin A or vitamin D treatment on the concentration of biogenic amines and their metabolites in the adult rat brain. Horm. Metab. Res. 41, 277–280 (2009)
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Tekes K , Gyenge M , Hantos M , Csaba G : Transgenerational hormonal imprinting caused by vitamin A and vitamin D treatment of newborn rats. Alterations in the biogenic amine contents of the adult brain. Brain Dev. 31, 666–670 (2009)
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Traber MG : Vitamin E, nuclear receptors and xenobiotic metabolism. Arch. Biochem. Biophys. 423, 6–11 (2004)
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Walker DM , Gore AC : Epigenetic impacts of endocrine disruptors in the brain. Front. Neuroendocrinol. 44, 1–26 (2017)
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Williams GR : Neurodevelopmental and neurophysiological actions of thyroid hormone. J. Neuroendocrinol. 20, 784–794 (2008)
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Zhou C , Assem M , Tay JC , Watkins PB , Blumberg B , Schuetz EG , Thummel KE : Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia. J. Clin. Invest. 116, 1703–1712 (2006)
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Zouboulis CC : The human skin as a hormone target and an endocrine gland. Hormones (Athens Greece) 3, 9–26 (2004)
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