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Gene–Environment Interactions

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (29 April 2016) | Viewed by 72628

Special Issue Editor

Director, W. Montague Cobb Research Laboratory, Howard University, Washington, DC 20059, USA
Interests: human genomics; human diversity and microevolution; epigenomic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Each day, as our sophistication in understanding genomics increases, our recognition of the impact of quantifiable measures of the environment also grows. Non-genetic factors continue to have major influences on gene expression. Our difficulty in assessing these interactions in the past, however, was due to several factors.

Foremost, perhaps, has been a historic reductionist mindset, favoring the juxtaposition of genes versus environment in understanding the phenotype. Greater knowledge has matured our thinking in the scientific community and has allowed this perspective to wane. Howevver, today, we are still limited by a paucity of well-quantified assessments of the environment and the specific impacts of complex environments on gene expression. What is emerging is a realization that, in considering gene-environment interactions, we can no longer treat the environment as if were static, uniform, and an invariable monolith. Additionally, our statistical capabilities have also advanced to the point that we have the means to evaluate specific, well-defined complex interactions. Computational systems biology, for example, empowers us to consider the influence of multiple, fluctuating environmental variables on gene expression patterns. We appear to be at the point now where we can truly begin to integrate genetic and environmental factors in specific case studies.

This Special Issue of International Journal of Molecular Sciences, “Gene–Environment Interactions”, will focus on case studies and theoretical approaches to the interactions of genes and diverse environmental factors. Authors are invited to submit manuscripts that detail the epigenomic and epigenetic effects of specific environmental variables on gene expression patterns, manuscripts that provide an evolutionary perspective on the integrated roles of environment and genetics in producing particular phenotypes, and manuscripts that highlight the multi-generational effects of gene–environment interactions.

Prof. Dr. Fatimah L. C. Jackson
Guest Editor

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Keywords

  • disease risk
  • ecogenetics
  • environmental exposures
  • high risk genotypes
  • development

Published Papers (11 papers)

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Research

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1600 KiB  
Article
Family Growth and Survival Response to Two Simulated Water Temperature Environments in the Sea Urchin Strongylocentrotus intermedius
by Yaqing Chang, Xiaofei Tian, Weijie Zhang, Fenjie Han, Shun Chen, Mi Zhou, Zhenguo Pang, Shoubing Qi and Wenping Feng
Int. J. Mol. Sci. 2016, 17(9), 1356; https://doi.org/10.3390/ijms17091356 - 29 Aug 2016
Cited by 17 | Viewed by 4216
Abstract
Heat tolerance is a target trait in the selective breeding of the sea urchin Strongylocentrotus intermedius, as it plays an important role in the survival and growth of cultured S. intermedius during summer. We investigated family growth and survival response to two [...] Read more.
Heat tolerance is a target trait in the selective breeding of the sea urchin Strongylocentrotus intermedius, as it plays an important role in the survival and growth of cultured S. intermedius during summer. We investigated family growth and survival response to two temperature treatments to evaluate the genotype by temperature interaction (GEI) in the family selection of S. intermedius. Sea urchins from 11 families were exposed to two simulated water temperature environments—high temperature (HE) and control temperature (CE)—for 12 months, with each experiment divided into four periods (P1, stress-free period I; P2, stress-full high period; P3, stress-response period; and P4, stress-free period II) based on the temperature changes and the survival. Test diameter (TD), body weight (BW), and survival rate (SR) in HE and CE were measured monthly. Effects of family, temperature, and family-temperature interaction on TD, BW, SR, and specific growth rate (SGR) for BW were examined. In CE, BW differed significantly between families in P2, P3, and P4, while TD differed significantly between families in P3 and P4 (p < 0.05). In HE, family had significant effects on BW in P4, and on TD in P3 and P4, while temperature had significant effects on SR, TD, and BW in P3 and P4 (p < 0.05). GEI effects were not significant for TD or BW; however, family ranking changes revealed the existence of GEI in SR. The GEI results indicate the necessity of applying family selection in CE and HE for SR, but not for TD or BW. These results may provide a guide for aquaculture and selective breeding of S. intermedius under temperature pressure. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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3484 KiB  
Article
A Nonlinear Model for Gene-Based Gene-Environment Interaction
by Jian Sa, Xu Liu, Tao He, Guifen Liu and Yuehua Cui
Int. J. Mol. Sci. 2016, 17(6), 882; https://doi.org/10.3390/ijms17060882 - 04 Jun 2016
Cited by 2 | Viewed by 5393
Abstract
A vast amount of literature has confirmed the role of gene-environment (G×E) interaction in the etiology of complex human diseases. Traditional methods are predominantly focused on the analysis of interaction between a single nucleotide polymorphism (SNP) and an environmental variable. Given that genes [...] Read more.
A vast amount of literature has confirmed the role of gene-environment (G×E) interaction in the etiology of complex human diseases. Traditional methods are predominantly focused on the analysis of interaction between a single nucleotide polymorphism (SNP) and an environmental variable. Given that genes are the functional units, it is crucial to understand how gene effects (rather than single SNP effects) are influenced by an environmental variable to affect disease risk. Motivated by the increasing awareness of the power of gene-based association analysis over single variant based approach, in this work, we proposed a sparse principle component regression (sPCR) model to understand the gene-based G×E interaction effect on complex disease. We first extracted the sparse principal components for SNPs in a gene, then the effect of each principal component was modeled by a varying-coefficient (VC) model. The model can jointly model variants in a gene in which their effects are nonlinearly influenced by an environmental variable. In addition, the varying-coefficient sPCR (VC-sPCR) model has nice interpretation property since the sparsity on the principal component loadings can tell the relative importance of the corresponding SNPs in each component. We applied our method to a human birth weight dataset in Thai population. We analyzed 12,005 genes across 22 chromosomes and found one significant interaction effect using the Bonferroni correction method and one suggestive interaction. The model performance was further evaluated through simulation studies. Our model provides a system approach to evaluate gene-based G×E interaction. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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2938 KiB  
Article
Over-Expression of GmGIa-Regulated Soybean miR172a Confers Early Flowering in Transgenic Arabidopsis thaliana
by Tao Wang, Ming-Yang Sun, Xue-Song Wang, Wen-Bin Li and Yong-Guang Li
Int. J. Mol. Sci. 2016, 17(5), 645; https://doi.org/10.3390/ijms17050645 - 29 Apr 2016
Cited by 25 | Viewed by 5608
Abstract
Flowering is a pivotal event in the life cycle of plants. miR172 has been widely confirmed to play critical roles in flowering time control by regulating its target gene expression in Arabidopsis. However, the role of its counterpart in soybean remains largely unclear. [...] Read more.
Flowering is a pivotal event in the life cycle of plants. miR172 has been widely confirmed to play critical roles in flowering time control by regulating its target gene expression in Arabidopsis. However, the role of its counterpart in soybean remains largely unclear. In the present study, we found that the gma-miR172a was regulated by a GIGANTEA ortholog, GmGIa, in soybean through miRNA metabolism. The expression analysis revealed that gma-miR172a has a pattern of diurnal rhythm expression and its abundance increased rapidly as plants grew until the initiation of flowering phase in soybean. One target gene of gma-miR172a, Glyma03g33470, was predicted and verified using a modified RLM 5′-RACE (RNA ligase-mediated rapid amplification of 5′ cDNA ends) assay. Overexpression of gma-miR172a exhibited an early flowering phenotype and the expression of FT, AP1 and LFY were simultaneously increased in gma-miR172a-transgenic Arabidopsis plants, suggesting that the early flowering phenotype was associated with up-regulation of these genes. The overexpression of the gma-miR172a-resistant version of Glyma03g33470 weakened early flowering phenotype in the toe1 mutant of Arabidopsis. Taken together, our results suggested that gma-miR172a played an important role in GmGIa-mediated flowering by repressing Glyma03g33470, which in turn increased the expression of FT, AP1 and LFY to promote flowering in soybean. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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6281 KiB  
Article
The AaDREB1 Transcription Factor from the Cold-Tolerant Plant Adonis amurensis Enhances Abiotic Stress Tolerance in Transgenic Plant
by Jun-Mei Zong, Xiao-Wei Li, Yuan-Hang Zhou, Fa-Wei Wang, Nan Wang, Yuan-Yuan Dong, Yan-Xi Yuan, Huan Chen, Xiu-Ming Liu, Na Yao and Hai-Yan Li
Int. J. Mol. Sci. 2016, 17(4), 611; https://doi.org/10.3390/ijms17040611 - 22 Apr 2016
Cited by 32 | Viewed by 5815
Abstract
Dehydration-responsive element binding (DREB) transcription factors (TFs) play important roles in the regulation of plant resistance to environmental stresses and can specifically bind to dehydration-responsive element/C-repeat element (DRE/CRT) proteins (G/ACCGAC) and activate expression of many stress-inducible genes. Here, we cloned and characterized a [...] Read more.
Dehydration-responsive element binding (DREB) transcription factors (TFs) play important roles in the regulation of plant resistance to environmental stresses and can specifically bind to dehydration-responsive element/C-repeat element (DRE/CRT) proteins (G/ACCGAC) and activate expression of many stress-inducible genes. Here, we cloned and characterized a novel gene (AaDREB1) encoding the DREB1 transcription factor from the cold-tolerant plant Adonis amurensis. Quantitative real-time (qRT)-PCR results indicated that AaDREB1 expression was induced by salt, drought, cold stress, and abscisic acid application. A yeast one-hybrid assay demonstrated that AaDREB1 encodes a transcription activator and specifically binds to DRE/CRT. Furthermore, transgenic Arabidopsis and rice harboring AaDREB1 showed enhanced tolerance to salt, drought, and low temperature. These results indicated that AaDREB1 might be useful in genetic engineering to improve plant stress tolerance. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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1254 KiB  
Article
Changes in Air CO2 Concentration Differentially Alter Transcript Levels of NtAQP1 and NtPIP2;1 Aquaporin Genes in Tobacco Leaves
by Francesca Secchi, Andrea Schubert and Claudio Lovisolo
Int. J. Mol. Sci. 2016, 17(4), 567; https://doi.org/10.3390/ijms17040567 - 14 Apr 2016
Cited by 6 | Viewed by 5098
Abstract
The aquaporin specific control on water versus carbon pathways in leaves is pivotal in controlling gas exchange and leaf hydraulics. We investigated whether Nicotiana tabacum aquaporin 1 (NtAQP1) and Nicotiana tabacum plasma membrane intrinsic protein 2;1 (NtPIP2;1) gene expression [...] Read more.
The aquaporin specific control on water versus carbon pathways in leaves is pivotal in controlling gas exchange and leaf hydraulics. We investigated whether Nicotiana tabacum aquaporin 1 (NtAQP1) and Nicotiana tabacum plasma membrane intrinsic protein 2;1 (NtPIP2;1) gene expression varies in tobacco leaves subjected to treatments with different CO2 concentrations (ranging from 0 to 800 ppm), inducing changes in photosynthesis, stomatal regulation and water evaporation from the leaf. Changes in air CO2 concentration ([CO2]) affected net photosynthesis (Pn) and leaf substomatal [CO2] (Ci). Pn was slightly negative at 0 ppm air CO2; it was one-third that of ambient controls at 200 ppm, and not different from controls at 800 ppm. Leaves fed with 800 ppm [CO2] showed one-third reduced stomatal conductance (gs) and transpiration (E), and their gs was in turn slightly lower than in 200 ppm– and in 0 ppm–treated leaves. The 800 ppm air [CO2] strongly impaired both NtAQP1 and NtPIP2;1 gene expression, whereas 0 ppm air [CO2], a concentration below any in vivo possible conditions and specifically chosen to maximize the gene expression alteration, increased only the NtAQP1 transcript level. We propose that NtAQP1 expression, an aquaporin devoted to CO2 transport, positively responds to CO2 scarcity in the air in the whole range 0–800 ppm. On the contrary, expression of NtPIP2;1, an aquaporin not devoted to CO2 transport, is related to water balance in the leaf, and changes in parallel with gs. These observations fit in a model where upregulation of leaf aquaporins is activated at low Ci, while downregulation occurs when high Ci saturates photosynthesis and causes stomatal closure. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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2646 KiB  
Article
Molecular Cloning and Expression Analysis of Eight PgWRKY Genes in Panax ginseng Responsive to Salt and Hormones
by Hao Xiu, Mohammed Nuruzzaman, Xiangqian Guo, Hongzhe Cao, Jingjia Huang, Xianghui Chen, Kunlu Wu, Ru Zhang, Yuzhao Huang, Junli Luo and Zhiyong Luo
Int. J. Mol. Sci. 2016, 17(3), 319; https://doi.org/10.3390/ijms17030319 - 04 Mar 2016
Cited by 28 | Viewed by 6339
Abstract
Despite the importance of WRKY genes in plant physiological processes, little is known about their roles in Panax ginseng C.A. Meyer. Forty-eight unigenes on this species were previously reported as WRKY transcripts using the next-generation sequencing (NGS) technology. Subsequently, one gene that encodes [...] Read more.
Despite the importance of WRKY genes in plant physiological processes, little is known about their roles in Panax ginseng C.A. Meyer. Forty-eight unigenes on this species were previously reported as WRKY transcripts using the next-generation sequencing (NGS) technology. Subsequently, one gene that encodes PgWRKY1 protein belonging to subgroup II-d was cloned and functionally characterized. In this study, eight WRKY genes from the NGS-based transcriptome sequencing dataset designated as PgWRKY2-9 have been cloned and characterized. The genes encoding WRKY proteins were assigned to WRKY Group II (one subgroup II-c, four subgroup II-d, and three subgroup II-e) based on phylogenetic analysis. The cDNAs of the cloned PgWRKYs encode putative proteins ranging from 194 to 358 amino acid residues, each of which includes one WRKYGQK sequence motif and one C2H2-type zinc-finger motif. Quantitative real-time PCR (qRT-PCR) analysis demonstrated that the eight analyzed PgWRKY genes were expressed at different levels in various organs including leaves, roots, adventitious roots, stems, and seeds. Importantly, the transcription responses of these PgWRKYs to methyl jasmonate (MeJA) showed that PgWRKY2, PgWRKY3, PgWRKY4, PgWRKY5, PgWRKY6, and PgWRKY7 were downregulated by MeJA treatment, while PgWRKY8 and PgWRKY9 were upregulated to varying degrees. Moreover, the PgWRKY genes increased or decreased by salicylic acid (SA), abscisic acid (ABA), and NaCl treatments. The results suggest that the PgWRKYs may be multiple stress–inducible genes responding to both salt and hormones. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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2691 KiB  
Article
Physiological Investigation and Transcriptome Analysis of Polyethylene Glycol (PEG)-Induced Dehydration Stress in Cassava
by Lili Fu, Zehong Ding, Bingying Han, Wei Hu, Yajun Li and Jiaming Zhang
Int. J. Mol. Sci. 2016, 17(3), 283; https://doi.org/10.3390/ijms17030283 - 25 Feb 2016
Cited by 79 | Viewed by 8433
Abstract
Cassava is an important tropical and sub-tropical root crop that is adapted to drought environment. However, severe drought stress significantly influences biomass accumulation and starchy root production. The mechanism underlying drought-tolerance remains obscure in cassava. In this study, changes of physiological characters and [...] Read more.
Cassava is an important tropical and sub-tropical root crop that is adapted to drought environment. However, severe drought stress significantly influences biomass accumulation and starchy root production. The mechanism underlying drought-tolerance remains obscure in cassava. In this study, changes of physiological characters and gene transcriptome profiles were investigated under dehydration stress simulated by polyethylene glycol (PEG) treatments. Five traits, including peroxidase (POD) activity, proline content, malondialdehyde (MDA), soluble sugar and soluble protein, were all dramatically induced in response to PEG treatment. RNA-seq analysis revealed a gradient decrease of differentially expressed (DE) gene number in tissues from bottom to top of a plant, suggesting that cassava root has a quicker response and more induced/depressed DE genes than leaves in response to drought. Overall, dynamic changes of gene expression profiles in cassava root and leaves were uncovered: genes related to glycolysis, abscisic acid and ethylene biosynthesis, lipid metabolism, protein degradation, and second metabolism of flavonoids were significantly induced, while genes associated with cell cycle/organization, cell wall synthesis and degradation, DNA synthesis and chromatin structure, protein synthesis, light reaction of photosynthesis, gibberelin pathways and abiotic stress were greatly depressed. Finally, novel pathways in ABA-dependent and ABA-independent regulatory networks underlying PEG-induced dehydration response in cassava were detected, and the RNA-Seq results of a subset of fifteen genes were confirmed by real-time PCR. The findings will improve our understanding of the mechanism related to dehydration stress-tolerance in cassava and will provide useful candidate genes for breeding of cassava varieties better adapted to drought environment. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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1510 KiB  
Article
Identification and Evolution of Functional Alleles of the Previously Described Pollen Specific Myrosinase Pseudogene AtTGG6 in Arabidopsis thaliana
by Lili Fu, Bingying Han, Deguan Tan, Meng Wang, Mei Ding and Jiaming Zhang
Int. J. Mol. Sci. 2016, 17(2), 262; https://doi.org/10.3390/ijms17020262 - 22 Feb 2016
Cited by 6 | Viewed by 4690
Abstract
Myrosinases are β-thioglucoside glucohydrolases and serve as defense mechanisms against insect pests and pathogens by producing toxic compounds. AtTGG6 in Arabidopsis thaliana was previously reported to be a myrosinase pseudogene but specifically expressed in pollen. However, we found that AlTGG6, an ortholog [...] Read more.
Myrosinases are β-thioglucoside glucohydrolases and serve as defense mechanisms against insect pests and pathogens by producing toxic compounds. AtTGG6 in Arabidopsis thaliana was previously reported to be a myrosinase pseudogene but specifically expressed in pollen. However, we found that AlTGG6, an ortholog to AtTGG6 in A. lyrata (an outcrossing relative of A. thaliana) was functional, suggesting that functional AtTGG6 alleles may still exist in A. thaliana. AtTGG6 alleles in 29 A. thaliana ecotypes were cloned and sequenced. Results indicate that ten alleles were functional and encoded Myr II type myrosinase of 512 amino acids, and myrosinase activity was confirmed by overexpressing AtTGG6 in Pichia pastoris. However, the 19 other ecotypes had disabled alleles with highly polymorphic frame-shift mutations and diversified sequences. Thirteen frame-shift mutation types were identified, which occurred independently many times in the evolutionary history within a few thousand years. The functional allele was expressed specifically in pollen similar to the disabled alleles but at a higher expression level, suggesting its role in defense of pollen against insect pests such as pollen beetles. However, the defense function may have become less critical after A. thaliana evolved to self-fertilization, and thus resulted in loss of function in most ecotypes. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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4016 KiB  
Article
CpLEA5, the Late Embryogenesis Abundant Protein Gene from Chimonanthus praecox, Possesses Low Temperature and Osmotic Resistances in Prokaryote and Eukaryotes
by Yiling Liu, Lixia Xie, Xilong Liang and Shihong Zhang
Int. J. Mol. Sci. 2015, 16(11), 26978-26990; https://doi.org/10.3390/ijms161126006 - 11 Nov 2015
Cited by 29 | Viewed by 5416
Abstract
Plants synthesize and accumulate a series of stress-resistance proteins to protect normal physiological activities under adverse conditions. Chimonanthus praecox which blooms in freezing weather accumulates late embryogenesis abundant proteins (LEAs) in flowers, but C. praecox LEAs are little reported. Here, we report a [...] Read more.
Plants synthesize and accumulate a series of stress-resistance proteins to protect normal physiological activities under adverse conditions. Chimonanthus praecox which blooms in freezing weather accumulates late embryogenesis abundant proteins (LEAs) in flowers, but C. praecox LEAs are little reported. Here, we report a group of five LEA genes of C. praecox (CpLEA5, KT727031). Prokaryotic-expressed CpLEA5 was employed in Escherichia coli to investigate bioactivities and membrane permeability at low-temperature. In comparison with the vacant strains, CpLEA5-containing strains survived in a 20% higher rate; and the degree of cell membrane damage in CpLEA5-containing strains was 55% of that of the vacant strains according to a conductivity test, revealing the low-temperature resistance of CpLEA5 in bacteria. CpLEA5 was also expressed in Pichia pastoris. Interestingly, besides low-temperature resistance, CpLEA5 conferred high resistance to salt and alkali in CpLEA5 overexpressing yeast. The CpLEA5 gene was transferred into Arabidopsis thaliana to also demonstrate CpLEA5 actions in plants. As expected, the transgenic lines were more resistant against low-temperature and drought while compared with the wild type. Taken together, CpLEA5-conferred resistances to several conditions in prokaryote and eukaryotes could have great value as a genetic technology to enhance osmotic stress and low-temperature tolerance. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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Review

Jump to: Research

376 KiB  
Review
Gene–Environment Interactions in Preventive Medicine: Current Status and Expectations for the Future
by Hiroto Narimatsu
Int. J. Mol. Sci. 2017, 18(2), 302; https://doi.org/10.3390/ijms18020302 - 30 Jan 2017
Cited by 12 | Viewed by 6187
Abstract
The progression of many common disorders involves a complex interplay of multiple factors, including numerous different genes and environmental factors. Gene–environmental cohort studies focus on the identification of risk factors that cannot be discovered by conventional epidemiological methodologies. Such epidemiological methodologies preclude precise [...] Read more.
The progression of many common disorders involves a complex interplay of multiple factors, including numerous different genes and environmental factors. Gene–environmental cohort studies focus on the identification of risk factors that cannot be discovered by conventional epidemiological methodologies. Such epidemiological methodologies preclude precise predictions, because the exact risk factors can be revealed only after detailed analyses of the interactions among multiple factors, that is, between genes and environmental factors. To date, these cohort studies have reported some promising results. However, the findings do not yet have sufficient clinical significance for the development of precise, personalized preventive medicine. Especially, some promising preliminary studies have been conducted in terms of the prevention of obesity. Large-scale validation studies of those preliminary studies, using a prospective cohort design and long follow-ups, will produce useful and practical evidence for the development of preventive medicine in the future. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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7776 KiB  
Review
Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases
by Mark Preciados, Changwon Yoo and Deodutta Roy
Int. J. Mol. Sci. 2016, 17(12), 2086; https://doi.org/10.3390/ijms17122086 - 13 Dec 2016
Cited by 68 | Viewed by 14682
Abstract
During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are [...] Read more.
During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD—APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF—underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely different from male human AD patients. AD-associated NRF1 target genes—APLP1, APP, GRIN1, GRIN2B, MAPT, PSEN2, PEN2, and IDE—are also regulated by E2. NRF1 regulates targets genes with diverse functions, including cell growth, apoptosis/autophagy, mitochondrial biogenesis, genomic instability, neurogenesis, neuroplasticity, synaptogenesis, and senescence. By activating or repressing the genes involved in cell proliferation, growth suppression, DNA damage/repair, apoptosis/autophagy, angiogenesis, estrogen signaling, neurogenesis, synaptogenesis, and senescence, and inducing a wide range of DNA damage, genomic instability and DNA methylation and transcriptional repression, NRF1 may act as a major regulator of EEDs-induced brain health deficits. In summary, estrogenic endocrine disrupting chemicals-modified genes in brain health deficits are part of both estrogen and NRF1 signaling pathways. Our findings suggest that in addition to estrogen signaling, EEDs influencing NRF1 regulated communities of genes across genomic and epigenomic multiple networks may contribute in the development of complex chronic human brain health disorders. Full article
(This article belongs to the Special Issue Gene–Environment Interactions)
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