Stage 1: from gametes to embryo-endometrium cross-talk; Stage, MeSH It is the comments and import statements in the code base of DNA. Cells. In this way, altered maternal nutrition may induce epigenetic changes in the global expression pattern of the fetus, which will trigger biological and psychological alterations in offsprings lifelong outcomes [136139]. DNA methylation defects in spermatozoa of male partners from couples experiencing recurrent pregnancy loss. Several studies and evidences report that precise chromatin modification patterns occur in the fetal membrane and decidua cells, changing dynamically during normal and pathological pregnancies [31]. Aristizabal MJ, Anreiter I, Halldorsdottir T, Odgers CL, McDade TW, Goldenberg A, Mostafavi S, Kobor MS, Binder EB, Sokolowski MB, ODonnell KJ. Hjort L, Martino D, Grunnet LG, Naeem H, Maksimovic J, Olsson AH, Zhang C, Ling C, Olsen SF, Saffery R, Vaag AA. Epigenetic definition, of or relating to epigenesis, or the successive differentiation of undifferentiated cells in an embryo. Fuemmeler BF, Dozmorov MG, Do EK, Zhang JJ, Grenier C, Huang Z, Maguire RL, Kollins SH, Hoyo C, Murphy SK. Eating disorders during gestation: implications for mothers health, fetal outcomes, and epigenetic changes. Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. 10.1093/hmg/ddl046 [. Altered methylation patterns of 10 imprinted genes (DLX5, DHCR24, VTRNA2-1, PHLDA2, NPA1, FAM50B, GNAS-AS1, PAX8-AS1, SHANK2, and COPG2IT1) have been also associated with reduced quality of movement, elevated indices of asymmetrical and non-optimal reflexes, and increased likelihood of physiological stress [126]. Main epigenetic processes involved in the regulation of pregnancy, -Transcription silencing (sporadically transcription permissive), -Protein recruitment (scaffolding &/or sponging), DNMT, DNA methyltransferase; TET, ten-eleven translocation methylcytosine dioxygenases; MBD4, methyl-CpG binding protein 4; TDG, thymine DNAglycosylase; (A), acetylation; (M), methylation; (P), phosphorylation; (U), ubiquitination; HATs, histone acetyltransferases; HDACs, histone deacetylases; HMTs, histone methyltransferases; HDMs, histone demethylases; DUBs, deubiquitinating enzymes; ncRNAs, non-coding RNAs; sncRNAs, short ncRNAs; siRNAs, short interfering RNAs; miRNAs, microRNAs; piRNAs, piwi interacting RNAs; lncRNAs, long ncRNAs; lincRNAs, long intergenic ncRNAs; ilncRNAs, intronic long ncRNAs; eRNAs, enhancer long ncRNAs; DMRs, differentially methylated regions; ICRs, imprinting control regions. eCollection 2022. Transgenerational epigenetic inheritance: from phenomena to molecular mechanisms. Unauthorized use of these marks is strictly prohibited. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development. 10.18632/aging.102864. Because folate deficiency in early pregnancy is associated with an increased risk of Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12. MicroRNA-31 is significantly elevated in both human endometrium and serum during the window of implantation: a potential biomarker for optimum receptivity. Gil-Ibez P, Bernal J, Morte B. Thyroid hormone regulation of gene expression in primary cerebrocortical cells: role of thyroid hormone receptor subtypes and interactions with retinoic acid and glucocorticoids. Jiang Y, Zou D, Li Y, Gu S, Dong J, Ma X, Xu S, Wang F, Huang JH. DNA methylation dynamics in the female germline and maternal-effect mutations that disrupt genomic imprinting. Cai S, Qiu A, Broekman BFP, Wong EQ, Gluckman PD, Godfrey KM, Saw SM, Soh S-E, Kwek K, Chong Y-S, Meaney MJ, Kramer MS, Rifkin-Graboi A, GUSTO study group The influence of gestational diabetes on neurodevelopment of children in the first two years of life: a prospective study. Mechanisms of implantation: strategies for successful pregnancy. Moreover, other EDs have been shown to interact with DNMTs and TETs enzymes, altering their activity in in vitro experiments [157]. See more. Schagdarsurengin U, Paradowska A, Steger K. Analysing the sperm epigenome: roles in early embryogenesis and assisted reproduction. Hamza M, Halayem S, Mrad R, Bourgou S, Charfi F, Belhadj A. Encephale. The .gov means its official. Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction. The neurological condition known as amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrigs disease, or motor neuron disease (MND), is a progressive condition that affects the nerve cells that regulate voluntary muscles [].ALS is still considered one of the rare diseases and its incidence worldwide is 2.75 Investigation towards miRNA and downstream transcriptional regulation are growing, while studies investigating histone modifications are still sparse [176]. The earliest stages of embryonic development are characterized by major epigenetic remodeling events that include parental DNA methylation erasure and reprogramming (with the exception of DMRs), chromatin folding establishment, and spatial reorganization of the genome [6567]. Teschendorff AE, Relton CL. Khambata K, Raut S, Deshpande S, Mohan S, Sonawane S, Gaonkar R, Ansari Z, Datar M, Bansal V, Patil A, Warke H, Balasinor NH. National Library of Medicine Regarding substances universally recognized as teratogens, one of the most widespread is valproic acid (VPA). Gueta K, Molotski N, Gerchikov N, Mor E, Savion S, Fein A, Toder V, Shomron N, Torchinsky A. Teratogen-induced alterations in microRNA-34, microRNA-125b and microRNA-155 expression: correlation with embryonic p53 genotype and limb phenotype. Hot spots of epigenetic action. Zhang L, Lu Q, Chang C. Epigenetics in health and disease. The British epidemiologist David Barker first introduced the concept that the womb may be more important than the home, emphasizing the role of the gestational environment as a regulatory staple in the development of the embryo, of the fetus and, ultimately, of the adult [1]. Some authors reported, in a prospective study of high-risk pregnancies, that 400 DMRs discriminate placentas from offspring later diagnosed with ASD compared to those not diagnosed with such disorders [124]. Yu S-L, Kim T-H, Han Y-H, Kang Y, Jeong D-U, Lee DC, Kang J, Park S-R. Transcriptomic analysis and competing endogenous RNA network in the human endometrium between proliferative and mid-secretory phases. Howerton CL, Bale TL. Fetal membrane epigenetics. The brain is an organ that consumes a lot of energy and absorbs a massive quantity of maternal resources during its growth and evolution. It is defined as an exclusive expression of either paternally or maternally derived allele of a gene, while the other allele is silenced via epigenetic reprogramming of germ cells in utero [ 1, 2, 3 ]. As a result, DNA methylation is mainly restricted to the transcribed gene bodies, while intergenic regions are hypomethylated [5759], as non-CpG hypermethylation plays an active role in gene expression regulation during oocyte maturation, potentially through the incorporation with transcription factors [57]. Besides placental 5-HT affecting neurobehavioral development, methylation of placental HTR2A (the receptor which mediates the effects of 5-HT) may also be implicated. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Argyraki M, Damdimopoulou P, Chatzimeletiou K, Grimbizis GF, Tarlatzis BC, Syrrou M, Lambropoulos A. Hum Reprod Update. Chen J, Xue Y. Knowledge of the phenomena related to such regulatory mechanisms carries a huge relevance in both physiology and pathophysiology. Zijlmans MAC, Riksen-Walraven JM, de Weerth C. Associations between maternal prenatal cortisol concentrations and child outcomes: a systematic review. Supecka-Ziemilska M, Wychowaski P, Puzianowska-Kuznicka M. Gestational diabetes mellitus affects offsprings epigenome. Epigenetics Paul Magbanua 54.2K views63 slides. Epigenetics in pregnancy. However, many mechanisms of transitory prenatal insults that result in postnatal dysregulation remain unclear [108]. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development. From embryo to adult: one carbon metabolism in stem cells. While many of the epigenetic mechanisms affecting early and late embryo development have long been known and studied, a promising new frontier comprising ncRNAs and neurodevelopmental factors has yet to be fully explored and understood, especially regarding the human species. Recent literature revealed the presence, in the endometrial fluid of both fertile and infertile women, of 12 sncRNAs strongly associated with biological functions related to immune response, extracellular matrix and cell junction, highlighting the different expression patterns in the two subpopulations and suggesting that sncRNA could be used as biomarkers of endometrial receptivity and implantation success [102]. Heerwagen MJ, Miller MR, Barbour LA, Friedman JE. WebEpigenetics: Introduction and Definition and the mechanism Mohit Adhikary 24.5K views52 slides. But this isn't completely true. Slider with three articles shown per slide. Furthermore, primary human endometrial endothelial cells (hEECs) were found to actively secrete large quantities of exosomes into the conditioned media, and labelling experiments with miR30-d revealed that miRNAs are internalized in vesicles and secreted in exosomes. doi: 10.1007/s10815-018-1343-x. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. doi: 10.3390/cells8121559. Therefore, we also recapitulate the effects of the most notable environmental factors that can affect pregnancy and prenatal development, such as maternal nutrition, stress hormones, microbiome, and teratogens, focusing on their ability to cause epigenetic modifications in the gestational environment and ultimately in the fetus. It is also undoubtedly important to reveal whether other teratogens can affect offspring in this way [182]. Recently, DNA methylation and miRNA expression patterns within the placenta have been also studied for potential associations with later neurobehavioral disruptions in the offspring [118]. Hopefully, in the future, DNA methylation status could be used as a biomarker of prenatal insults for tobacco exposure as well. Embryoepithelium interactions during implantation at a glance. Epigenetic regulation of endometrium during the menstrual cycle. Pregnancy-associated miRNA-clusters. Further processes of vascular remodeling, trophoblastic cellular migration, and immune regulation allow the formation of the placenta, a transient organ that connects the fetus to the mother [103]. -, Kurian NK, Modi D. Extracellular vesicle mediated embryo-endometrial cross talk during implantation and in pregnancy. May play critical role in cancer, depression, psychosomatic diseases The developing brain tissue requires considerable nutritional intake and it is particularly susceptible to overabundance or insufficiency of specific nutrients and growth factors [108, 110, 111]. Kurian NK, Modi D. Extracellular vesicle mediated embryo-endometrial cross talk during implantation and in pregnancy. Rauschert S, Melton PE, Burdge G, Craig JM, Godfrey KM, Holbrook JD, Lillycrop K, Mori TA, Beilin LJ, Oddy WH, Pennell C, Huang R-C. Maternal smoking during pregnancy induces persistent epigenetic changes into adolescence, independent of postnatal smoke exposure and is associated with cardiometabolic risk. The term decidualization defines the functional and morphological transition of the endometrial cells to form the cellular environment into which the blastocyst is able to implantitself. 2022 Sep 15;14(18):3799. doi: 10.3390/nu14183799. These compounds exhibit weak steroid-like activity and therefore can affect reproductive development along multiple points including the hypothalamus and the gonad. Grewal J, Carmichael SL, Ma C, Lammer EJ, Shaw GM. Ornoy A, Becker M, Weinstein-Fudim L, Ergaz Z. S-Adenosine methionine (SAMe) and valproic acid (VPA) as epigenetic modulators: special emphasis on their interactions affecting nervous tissue during pregnancy. The peroxisome proliferator-activated receptors under epigenetic control in placental metabolism and fetal development. Placental miRNome studies have also demonstrated its importance towards the coordination and modulation of the placental transcriptome [110, 111]. The epigenomic changes, due to prenatal exposure to ED, include altered global DNA methylation, gene specific CpG methylation, and microRNA expression [155]. 8600 Rockville Pike During gametogenesis and then again in the early moments after fertilization, mammals undergo a two-step DNA methylation reprogramming that affects more than 80% of the genome. Zhao L-Y, Song J, Liu Y, Song C-X, Yi C. Mapping the epigenetic modifications of DNA and RNA. The EDs most commonly associated with reproductive abnormalities are the xenoestrogens such as Bisphenol-A (BPA), polychlorinated biphenyls (PCBs), and antiandrogens such as phthalates. The epigenetic code is determined by several mechanisms that affect gene expression, the most well-known of which is DNA methylation (See Figure 1). The human sperm epigenome and its potential role in embryonic development. Pathological epigenetic alterations are particularly important in feto-materal medicine. This hypothesis supports both a connection between epigenetic regulation of the leptin receptor and the communication of fundamental information to the fetal brain and also a certain sex-specificity in these results. The role of epigenetic mechanisms in the regulation of gene expression in the cyclical endometrium. Rossetto D, Avvakumov N, Ct J. Histone phosphorylation: a chromatin modification involved in diverse nuclear events. Despite the promising advancements in the knowledge of epigenetics in pregnancy, more experience and data on this topic are still needed. Many signals regulate chromatin activation or repression; among these, those related to nutrient availability are relevant for epigenetic programming in the placenta. Sperm epigenetic abnormalities are associated with infertility, reduced embryogenesis capability, and alterations in early embryo development [50, 51], and the study of sperm epigenome is being evaluated as a potential diagnostic tool for idiopathic recurrent pregnancy loss and infertility [47, 5055]. Accessibility In the oocytes, de novo DNA methylation does not start as immediately as in their male counterparts and appears to be largely dispensable for the early oocyte development [56]. National Library of Medicine DNA methylation in babies born to nonsmoking mothers exposed to secondhand smoke during pregnancy: an epigenome-wide association study. Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J, Surani MA. This result probably reflects the numerous confounding factors that act synergistically during pregnancy and in the postnatal period [132]. Alcohol-related neonatal abnormalities are commonly referred to as fetal alcohol spectrum disorder (FASD) [160]. However, a recent review concluded that most of the published papers on this topic did not reveal a significant association between maternal cortisol in pregnancy and poorer offspring birth outcomes, lower cognitive outcomes, lower cognitive/motor development, or more behavioral problems in infancy and childhood. WebEpigenetics definition, the study of the process by which genetic information is translated into the substance and behavior of an organism: specifically, the study of the way in The bright and dark side of DNA methylation: a matter of balance. FOIA Morales-Prieto DM, Ospina-Prieto S, Chaiwangyen W, Schoenleben M, Markert UR. Skvortsova K, Iovino N, Bogdanovi O. Cuman C, Van Sinderen M, Gantier MP, Rainczuk K, Sorby K, Rombauts L, Osianlis T, Dimitriadis E. Human blastocyst secreted microRNA regulate endometrial epithelial cell adhesion. Effects of prenatal exposure to endocrine disruptors and toxic metals on the fetal epigenome. Several experiments showed that exosomes loaded with miR-30d were secreted from hEECs and could be internalized by trophoblastic cells of murine embryos adhered to hEECs [96]. miR-30b and miR-30d were also consistently found to be elevated in the mid-secretory as compared with the proliferative phase. A pivotal role in the fetal stage of pregnancy is played by the amniochorionic membranes, which act as the feto-maternal interface, as they exhibit characteristic chromatin modification patterns, DNA (CpG) methylation, histone modifications, and non-coding RNA transcriptomes, whose dynamic changes during normal and pathological pregnancies are an important contributor to gene regulation throughout pregnancy [31]. These effects are regulated by alteration in theepigenetic programming. Warning JC, McCracken SA, Morris JM. A better comprehension of the underlying mechanisms and their consequences could therefore improve diagnosis and treatment of human infertility and diseases. See this image and copyright information in PMC. Konwar C, Price EM, Wang LQ, Wilson SL, Terry J, Robinson WP. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, van Montfrans GA, Michels RP, Bleker OP. In mice, female placental tissue has higher amounts of global DNA methylation compared to male placentas, which may confer females additional protection from constant alterations in gene expression due to environmental insults [108, 120122]. Self-reported pregnancy exposures and placental DNA methylation in the MARBLES prospective autism sibling study. Esteller M. Non-coding RNAs in human disease. The epigenetic code can be altered by environmental exposures such as chemicals, nutrition and stress, especially in early life. The analysis of correlations between the expression pattern of the miRNAs tested in the study and cyclophosphamide induced limb phenotypes implies that miRNAs regulating apoptosis may differ from each other with respect to their functional role in teratogenesis [181]. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. Angeloni A, Bogdanovic O. Enhancer DNA methylation: implications for gene regulation. Histone mono-ubiquitination has a crucial role in protein translocation, DNA damage signaling, and regulation of transcription. Gestational valproic acid exposure induces epigenetic modifications in murine decidua. Early life stress acts in different ways in different tissues, altering gene expression and inducing epigenetic modifications (e.g., increased or reduced DNA methylation or histone acetylation in many brain regions at the same time) [96]. Bommarito PA, Martin E, Fry RC. One of the best known and most studied teratogens is ethanol, for it can cause a wide range of developmental abnormalities. In this scenario, the X-linked enzyme O-linked-N-acetylglucosamine transferase (OGT) seems to have a fundamental role in neurodevelopmental organization [108, 110, 115118]. The signaling of insulin, IGF-1 (insulin-like growth factor-1), and leptin receptors located at the maternalfetal interface promotes amino acid transporter activity in trophoblast cells, combining maternal nutritional state to placenta function and, consequently, invalidating the accessibility of nutrients diffusing into the fetal circulation [119]. Anvar Z, Chakchouk I, Demond H, Sharif M, Kelsey G, Van den Veyver IB. Hum Mol Genet 15 Spec No 1:R1729. Maccani MA, Padbury JF, Lester BM, Knopik VS, Marsit CJ. doi: 10.1152/ajpendo.00372.2015. A better understanding of epigenetic regulation in pregnancy could in fact prove valuable towards a better management of both physiological pregnancies and assisted reproduction treatments, other than allowing to better comprehend the origin of multifactorial pathological conditions such as neurodevelopmental disorders. Rivera RM, Ross JW. Exposure to EDs starts during fetal life and continues after birth: the link between prenatal exposures and latent health outcomes suggests that these exposures may result in long-term epigenetic reprogramming. This period of receptivity, called window of implantation [73], is short and results from the programmed sequence of the action of estrogen and progesterone on the endometrium via multiple paracrine, juxtacrine, and autocrine signaling [26, 74]. Retis-Resendiz AM, Gonzlez-Garca IN, Len-Jurez M, Camacho-Arroyo I, Cerbn M, Vzquez-Martnez ER. Gansen A, Tth K, Schwarz N, Langowski J. Extensive evidence has progressively emerged that the gestational environment determines a remarkable impact on an epigenetic level, at least with two different mechanisms: by directly regulating the stages of implantation and placentation; and widely remodeling epigenetic patterns during prenatal development, thus determining long-term outcomes in the offspring [4, 5, 710]. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new Careers. doi: 10.1152/ajpregu.00310.2010. Federal government websites often end in .gov or .mil. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Hansel, Gretel, and the consequences of failing to remove histone methylation breadcrumbs. In addition to determining parent-of-origin specific gene expression by genomic imprinting, the epigenetic reprogramming that happens during gametogenesis regulates gametes development, and its disruption can also reverberate in the zygote, embryo, and postnatal life. VPA is a well-tolerated antiepileptic drug and mood stabilizer that is used for the treatment of epilepsy and other non-psychiatric diseases like Alzheimer, HIV, and cancer [178]. 8600 Rockville Pike Silver MJ, Saffari A, Kessler NJ, Chandak GR, Fall CHD, Issarapu P, Dedaniya A, Betts M, Moore SE, Routledge MN, Herceg Z, Cuenin C, Derakhshan M, James PT, Monk D, Prentice AM. Even second-hand smoke exposure among non-smoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. Stage 1: from gametes to embryo-endometrium cross-talk; Stage 2: from placenta-fetus cross-talk to brain development, with an overview on environmental factors as well (nutrition and teratogens). The addition of a methyl group to the fifth carbon of the pyrimidine cytosine ring determines long-term silencing in processes such as genomic imprinting, tissue-specific regulation of gene expression, X-chromosome inactivation, and silencing of repetitive DNA elements. Macklon NS, Brosens JJ. The human endometrium as a sensor of embryo quality. Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children. ~1000 genes are involved in epigenetic control the contents by NLM or the National Institutes of Health. Shallie PD, Naicker T. The placenta as a window to the brain: a review on the role of placental markers in prenatal programming of neurodevelopment. The precision and the timing of such processes are pivotal for avoiding developmental defects or embryonic lethality, as an incorrect establishment of the embryonic epigenome would cause a defective zygotic genome activation (ZGA). WebIn this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of Placental HTR2A methylation is associated with infant neurobehavioral outcomes. Epigenetics is the level of control that sits above the genes and helps determine which genes are turned on and which genes are turned off. Chemical modifications to either the DNA, or structures associated with DNA, alter gene expression, without changes to the DNA sequence. Disclaimer. Am J Physiol Regul Integr Comp Physiol. Also, hEECs have been demonstrated to be able to uptake embryo-derived miRNAs, such as the embryoendometrial adhesion inhibitor miR-661 [101]. Guo S-W. According to Tochigi et al. The fetal and infant origins of adult disease. Associations of diet and physical activity with risk for gestational diabetes mellitus: a systematic review and meta-analysis. It is also specifically vulnerable to modifications in placental activity. In multicellular eukaryotes, DNA methylation mostly occurs at cytosines of CpG (CphosphateG) dinucleotides; highly methylated sequences can also be found in satellite DNAs, repetitive element and non-repetitive intergenic DNA. WebEPIGENETICS COURSERA CLASS: LECTURE WEEK 1 ~25,000 genes in humans but not all are used at same time in all cells. Casati L, Sendra R, Sibilia V, Celotti F. Endocrine disrupters: the new players able to affect the epigenome. Cigarette smoke creates alterations in DNA methylation of cord blood and placenta, histone modifications, and miRNA expression. Loss of miR-542-3p enhances IGFBP-1 expression in decidualizing human endometrial stromal cells. Elbracht M, Mackay D, Begemann M, Kagan KO, Eggermann T. Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences. Emerging roles of non-coding RNAs in epigenetic regulation. Extracellular vesicles mediated early embryo-maternal interactions. Many of these transcripts are in fact necessary for proper targeting of histone modifying complexes or participate in the DNA methylation process and genomic imprinting. J Assist Reprod Genet. WebEpigenetics is the study of non-genotoxic, reversible, heritable mechanisms that influence gene expression without changing the DNA sequence. Bellanti JA. There is also growing evidence that variants in the maternal genome affecting the imprinting status of the oocyte could cause MLID [44]. While it is known that most human transcripts are not translated, many of them actively participate in essential cellular functions nonetheless. Histone ubiquitination: triggering gene activity. VPA interacts with the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) and blocks voltage-gated ion channels. Best JD, Carey N. The epigenetics of normal pregnancy. Epigenetic regulation during early embryogenesis - Epigenetic regulation during early embryogenesis reprogramming and remodelling Helena Fulkova Istitute of Animal Science, www.vuzv.cz helena PowerPoint PPT presentation | free to view Diabetes in Pregnancy - Embryogenesis. Carrell DT. Lendvai , Deutsch MJ, Plsch T, Ensenauer R. Am J Physiol Endocrinol Metab. We present a case report of a 73-year-old woman suffering from bulbar onset ALS with a 4-month history of progressive dysphagia and dyspnea. Prenatal programing: at the intersection of maternal stress and immune activation. 2022 Sep 28;15(10):1203. doi: 10.3390/ph15101203. Moreover, the miRNA-200 family (miR-200a, miR-200b, miR200c, miR-141, and miR-429) showed a differential expression in the receptive phase as well, when they appear to be downregulated [89].
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