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Fetal Neurodevelopment The fetal developing central nervous system may be more vulnerable to environmental disturbances because unlike other systems it develops over a much longer period of time, it has limited repair capacities, the blood-brain barrier is not fully developed in utero, and the sensitivity of neurotransmitter systems, which is set during sensitive developmental periods, has an effect on the organism’s responses to all subsequent experience. Pathik Wadhwa (2005- “Behavioral perinatology” in Perinatal Stress, Mood and Anxiety Disorders: from Bench to Bedside edited by A. Riecher-Rössler and M. Steiner for Karger) reported a series of experiments in which it was demonstrated that the 32 week old human fetus may very well be capable of detecting, habituating and dehabituating to external stimuli (in this research vibroacoustic stimuli were used). This series of studies strongly suggests that by the early third trimester, the human fetal central nervous system is capable of learning and memory. Environmental experience (e.g., perturbations from CRH, cortisol?) seems to be recorded somatically. Prenatal and perinatal stress are considered established obstetric risk factors, e.g., women reporting high levels of prenatal and perinatal stress are twice as likely to experience an adverse outcome in pregnancy as women reporting low levels of stress. Stress-related physiological parameters such as placental CRH (corticotropin releasing hormone) and proinflammatory cytokines have been demonstrated to significantly predict the risk of adverse fetal developmental outcomes, particularly if experienced earlier in gestation. The epigenetic framework of development is quite important to keep in mind when considering the implications of this research. Jean-Pierre Changeux (2004- The Physiology of Truth: Neuroscience and Human Knowledge published by Harvard University Press) noted that the word ‘epigenetic’ is composed of two Greek roots: epi, which means ‘on’ or ‘upon’ and ‘genesis’ which means ‘birth.’ He used the term to underscore the impact of learning and the environment upon gene function. Epigenetics has been referred to as a “second, largely secret code” (Kramer 2005). In 2003, Europe organized a “human epigenome project” and in 2004, the Center for Epigenetics of Common Human Disease was established at Johns Hopkins University. Kramer (2005) has defined epigenetics as “the study of stable alterations in gene expression by nongenetic mechanisms [I would say processes] resulting in stable alterations in phenotype” (p. 25). In a deep sense, epigenetics is a form of biological or environmental programming in which the mother transmits to the offspring a form of forecasting of likely environmental conditions to be faced by the latter. Arturas Petronis (2004) defined epigenetics: “By definition, epigenetics refers to regulation of gene expressions that are controlled by heritable but potentially reversible changes in DNA methylation and/or chromatin structure” (p.175-in “Schizophrenia, neurodevelopment, and epigenetics” in Neurodevelopment and Schizophrenia edited by Matcheri Keshavan, James Kennedy & Robin Murray in 2004 for Cambridge University Press). A large number of genes exhibit an inverse correlation between the degree of methylation and gene expression, which lends support to an increasing body of experimental evidence suggesting that epigenetic modification is closely involved in the regulation of the expression of genes. One of the processes of epigenetic regulation of genes is related to methylation of the binding sites of transcription factors, leading to a change in the affinity of these factors for the regulatory sequences of these specific genes. This seems to be linked to another type of epigenetic regulation, that is, various types of histone modification. DNA is wrapped around histone complexes to form nucleosomes-depending on DNA and histone modifications, chromatin can be transcriptionally competent or not. Transcriptionally competent chromatin is normally enriched with acetylated histones, while transcriptionally silent chromatin is deacetylated. The interaction of DNA methylation and histone acetylation shows that the two types of epigenetic regulation act in concert. Epigenetic factors play a role in DNA mutagenesis and repair as well as in DNA recombination and possibly replication. Epigenetic patterns are transmitted similarly to DNA sequences, from maternal chromatids to daughter chromatids during mitotic divisions, and transmission of this epigenetic status is termed the “epigenetic inheritance system.” Unlike DNA sequences, which exhibit almost complete interclonal fidelity, epigenetics usually exhibits only partial stability. The partial stability of epigenetic modification is termed “epigenetic metastability.” There is evidence that some epigenetic signals escape erasure during maturation of gametes and, importantly, can be transmitted across generation (inducible defenses against predatory threat, as in the transgenerational transmission of trauma?). Two key aspects of epigenetic modification of the genome make epigenetics very relevant to schizophrenia. First, epigenetic modifications of DNA and chromatin orchestrates the activities of the genome, including regulation of gene expression. Epigenetic metastability is the second key aspect of relevance to schizophrenia. Epigenetic regulation of genes undergoes significant reorganization during development and aging as well as under the influence of extracellular factors (e.g., the hormonal status of the organism-cortisol expression during times of threat?) or environmental factors. Epigenetic regulation represents the dynamic feature of a gene and genome, whereas most of the DNA sequences do not alter during the life of the individual. Time of onset of schizophrenia may correlate with major hormonal (in particular cortisol hormonal expression) rearrangements in the individual. Epigenetic status of the gene is one of the targets of hormone action. Various hormones have a significant impact on gene expression, and this is secured by changing chromatin conformation and/or local patterns of gene methylation. A disease process may be initiated by hormone (e.g., cortisol)-mediated epigenetic changes in critical genes. Because of its enormous complexity, the human brain is likely to be susceptible to even mild epigenetic malfunction, which might lead to a wide variety of small morphological and functional changes in the developing brain. Epigenetic aberrations (epimutations) may originate from the following sources acting individually or in concert: epimutations, because of epigenetic metastability, can be inherited through the germline; epimutations can be caused by environmental factors; epigenetic aberrations may be generated by stochastic events in the embryonic cells. Wadhwa (2005) noted: “...it appears that fetal developmental processes ultimately represent the dynamic interplay between two sets of information systems (i.e.., fetal and maternal DNA) and two sets of cellular machinery (i.e., the fetal and maternal environments). It is crucial to identify the genetic and environmental determinants of fetal development, and to model the gene, environment, and maternal-fetal interactions that may underlie the risk of pathophysiological outcomes. In this context, the genetic architecture of fetal development and parturition is defined as the number of loci, their genomic positions, the number of functional alleles per locus, and the patterns of dominance, epistasis, pleiotropy, and gene-environment interactions that characterize the transition from genotype to phenotype” (p. 64). Genomic imprinting is an epigenetic process by which certain genes become suppressed on one of the two parental alleles. Its dysregulation may result in disease. Recent evidence suggests that stress can dysregulate the genomic imprinting process during development. Research with mice demonstrated that environmental stress affects the somatic maintenance of epigenetic marks at imprinted loci. These alterations may be attributed to changes in the methylation patterns, and are associated with aberrant growth and morphology at fetal and perinatal stages of development. However, nonimprinted genes can also undergo epigenetic change in response to environmental perturbations. As Wadhwa (2005) pointed out: “...a recent study in rodents reported that the choice of exon usage in the glucocorticoid receptor gene is altered in both prenatal glucocorticoid exposure and neonatal behavioral manipulation via histone acetylation and DNA methylation in a transcriptional factor binding site, and that these changes persist throughout life as manifested in altered HPA [hypothalamic-pituitary-adrenal] activity” (p.64). In my paper “The schizophrenias: Neuroscience, Neurophenomenological and Psychoanalytic Perspectives,” I noted the following on the connection between prenatal stress and later rates of schizophrenia: “The link between exposure to stress during gestation and subsequent schizophrenia was suggested by a study that prenatal death of father was associated with increased risk of schizophrenia (Kuh & Ben-Sholomo 1997). In a population-based study on increased risk of schizophrenia, it was observed that subjects exposed during the first trimester of pregnancy to the stress of invasion by the Nazi army in the Netherlands had increased rates of schizophrenia (van Os & Selten 1998-”Prenatal exposure to maternal stress and subsequent schizophrenia”. British Journal of Psychiatry, 172, 324-326). An additional population-based study conducted in the Netherlands discovered a (non-significant) increased risk of developing schizophrenia in subjects prenatally exposed to the 1953 Dutch flood disaster (Selten, van der Graaf, et al 1999-”Psychotic illness after prenatal exposure to the 1953 Dutch flood disaster.” Schizophrenia Research, 35, 243-245). Rates of schizophrenia were significantly higher in subjects whose mothers were told of their husbands’ deaths during the war between Finland and Russia while in the 2nd and 3rd trimester as opposed to hearing the news after birth. I wonder if the connection between maternal starvation and later development of schizophrenia made by Susser & Lin (1992-”Schizophrenia after prenatal exposure to Dutch hunger winter of 1944-1945,” Archives of General Psychiatry, 49, 983-988), could also be contributed to by the effects of maternal stress secondary to a lack of food supply. Verdoux and Sutter (2002-”Obstetrical complications, maternal psychopathology, and the risk of psychosis” ) noted: “The association between prenatal exposure to maternal stress and later schizophrenia may be mediated by the direct impact of stress, such as fetal hypoxia induced by vasoconstriction; or more indirectly, by increasing the risk of OC’s [obstetrical complications], such as prematurity, or by increasing the risk of maternal prenatal or postnatal depression” (p.108). I believe that the above research studies, performed at molecular and epidemiological levels, are a serious challenge to reductionistic views and models of the schizophrenias which make no or little room for the impact of social environmental factors, not just in the course and outcome of these disorders, but in their initiation as well. Brian Koehler PhD |