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Neurodevelopmental disorders resulting from toxic chemicals and how they can be prevented.

Neurodevelopmental disorders resulting from toxic chemicals and how they can be prevented.

What are some n? Do you think these disorders can be prevented? If so, how? If not, why not? 150 words and refs

What is psychopharmacology? What are some positive aspects related to psychopharmacology? What are some drawbacks? 150 words and refs.

Neurodevelopmental conditions are a small grouping of situations characterized by impairments of societal skills or knowledge with beginning from the developmental period of time. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), they include intellectual disability (Intellectual Developmental Disorder), communication disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), specific learning disorders, and motor disorders [1]. In 2011–2013, the estimated prevalence for ASD and other neurodevelopmental disabilities in children aged 3 to 17 years in the United States were 2.24% (1 in 45) and 3.57% (1 in 28), respectively [2]. Alarmingly, The Autism and Developmental Disabilities Monitoring (ADDM) Network that surveils children aged 8 years showed that the prevalence of ASD has increased from 0.66% to 1.46% over 10 years from 2002 to 2012 [3, 4]. Similarly, the prevalence of ADHD in children from 3 to 17 years also showed a 25.64% increase from 7.8% to 9.8% from 2003 to 2015 [5, 6]. The reasons for the increasing trend in ASD and ADHD are still controversial; explanations include changes in diagnostic criteria, reporting methods, or other factors such as environment, culture, and social-economic status that may affect the prevalence of neurodevelopmental disorders [7–9]. A previous study found indeed that the changes in diagnostic criteria alone account for only 33%, and a combination of changes in diagnostic criteria and reporting methods account for 60% of the increase in prevalence of ASD [7]. The search for etiologic and risk factors of neurodevelopmental disorders remains therefore an urgent issue and calls for further monitoring and research.

From the 1980s, epidemiologic studies by Barker et al. in England and Wales found out that areas with higher ischemic coronary disease mortality rates also had substantial infant mortality costs at the time when the seen age group is in its very early child years. A birth cohort study from 1911 by the same group found that the lower the birth weight, the higher the cardiovascular disease mortality rate, hypertension, and impaired glucose tolerance rate [10–13]. From these findings, Barker et al. proposed an “adult-onset of fetal origin” hypothesis called “Barker’s hypothesis,” stating that a low nutritional environment in the fetal stage increases the risk of chronic diseases in adulthood, which is the concept underlying the Developmental Origin of Health and Disease (DOHaD) [14]. The DOHaD concept is that the fetal-childhood environment affects the risk of chronic diseases in adulthood, based on knowledge obtained from epidemiological assessments of birth cohort studies. Research on developmental biology and human and animal physiology showed that the environment of fetal and early childhood have strong effects on development, health maintenance, and incidents of disease [15]. Based on the DOHaD theory, obesity, diabetes, and mental illness tend to develop in children born from women who are exposed to starvation during wartime [16–18]. Furthermore, folate and vitamin deficiency in the mother during pregnancy increases the risk of neurodevelopmental disorder [19–21]. In addition to maternal malnutrition, maternal stress due to various reasons is associated with child behavioral problems including ASD and ADHD [22–25].

Not restricted to maternal tension or poor nutrition, epidemiological reports have associated maternal exposure to environment toxicants and neurodevelopmental problems, specifically ASD and ADHD [26, 27]. Here, we focus on reviewing the relationship between maternal exposure to environmental toxicants and neurodevelopmental disorders and propose epigenetics as the linking mechanism.

Epigenetics is described as “a stably heritable phenotype caused by changes in a chromosome without adjustments from the DNA sequence” [28]. Thus, epigenetic mechanisms rely on DNA methylation, histone modification, histone variation, or noncoding RNAs, which change the chromatin structure and consequently control gene expression. Many conditions that fall under the term “neurodevelopmental disorders” are related to epigenetic abnormalities, namely the Prader-Willi syndrome, Angelman syndrome, ICF syndrome, and Rett syndrome.

Genomic imprinting may be the concept underlying epigenetics, released twenty years ago. Specifically, in genomic imprinting, only one allele of a gene is expressed, depending on its parental origin. To date, more than 70 imprinted genes are identified in the human genome, together with a number of related diseases named “imprinting disorders” [29]. The Prader-Willi syndrome and Angelman syndrome are two illustrative examples for imprinting disorders originating in the 15q11-13 imprinted region. In this region, normally, the paternally derived chromosome expresses several genes such as small nuclear ribonucleoprotein polypeptide N (SNRPN), SNRPN upstream reading frame (SNURF), small nucleolar RNA, C/D box 116 cluster (SNORD116), and melanoma-associated antigen (MAGE) family L2 (MAGEL2), while ubiquitin protein ligase E3A (UBE3A) is expressed from the maternally derived chromosome specifically in neurons. The Prader-Willi syndrome, a neurodevelopmental disorder characterized by a short stature, muscle tension reduction, overeating and subsequent obesity, diabetes, and personality persistence, is caused by mutation or deletion of the paternally derived chromosome or by a maternal uniparental disomy (both chromosomes 15 were derived from the mother) [30]. The Angelman syndrome, characterized by intractable epilepsy and severe developmental delay, is caused by a genomic imprinting abnormality of the 15q11-q13 region, similar to the Prader-Willi syndrome, but its pattern is reversed. The causative gene is the UBE3A gene, expressed on the maternal chromosome but not the paternal chromosome in neurons [31]. In addition to the loss of gene expression in the 15q11-13 region, which results in the Prader-Willi syndrome or Angelman syndrome according to the parental origin of the chromosome, overexpression of genes in this locus results in a different disorder: the 15q11-13 duplication syndrome (Dup15q). The duplication is almost always of maternal origin and the disease is characterized by hypotonia, speech disorder, behavior disorders, abnormal EEG, and developmental delay with other associated symptoms such as autism and seizures ]. Very recently, a large whole-genome bisulfite sequencing (WGBS) analysis on the human brain and neuronal cell culture model of Dup15q revealed a global decrease in DNA methylation in both CpG regions and long intersperse element 1 (LINE-1) repetitive elements. Furthermore, when compared to control samples, gene ontology analyses in the same study found that the differentially methylated regions are enriched for genes related to cell adhesion, brain, calcium channel, and membrane, many of which are known to have functions at neuronal synapses and are related to ASD [33]. More importantly, the authors also observed overlapped changes in DNA methylation and gene expression between neuronal cells exposed to polychlorinated biphenyl (PCB 95), an environmental toxicant, Dup15 model cells, and Dup15q model cells exposed to PCB 95, demonstrating an effect of environmental toxicant on neuronal genes via an epigenetic mechanism, which will be discussed later in this review. Together with previous studies performed on postmortem human brain tissue, the results have suggested that epigenetic alterations, together with genetic dosage, contributed to the changes in gene expression in the pathology of the disease. The fact that loss or enhanced function of these imprinted genes leads to developmental disorders implies the importance of proper gene expression in neurodevelopment.