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 ( ), 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, , 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, , PCBs, or metalloestrogens. Many genes modified by EEDs are common targets of both 17 I2-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- < i > APOE < /i >, < i > APP < /i >, < i > ATP5A1 < /i >, < i > CALM1 < /i >, < i > CASP3 < /i >, < i > GSK3B < /i >, < i > IL1B < /i >, < i > MAPT < /i >, < i > PSEN2 < /i > and < i > TNF- < /i > 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: < i > APBB2 < /i >, < i > DPYSL2 < /i >, < i > EIF2S1 < /i >, < i > ENO1 < /i >, < i > MAPT < /i >, and < i > PAXIP1 < /i >. These genes are also responsive to the following EEDs: ethinyl estradiol (< i > APBB2 < /i >, < i > DPYSL2 < /i >, < i > EIF2S1 < /i >, < i > ENO1 < /i >, < i > MAPT < /i >, and < i > PAXIP1 < /i >), (< i > APBB2 < /i >, < i > EIF2S1 < /i >, < i > ENO1 < /i >, < i > MAPT < /i >, and < i > PAXIP1 < /i >), (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (< i > DPYSL2 < /i > and < i > MAPT < /i >). 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- < i > APLP1 < /i >, < i > APP < /i >, < i > GRIN1 < /i >, < i > GRIN2B < /i >, < i > MAPT < /i >, < i > PSEN2 < /i >, < i > PEN2 < /i >, and < i > IDE < /i > -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.
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This project is supported by the Canadian Institutes of Health Research (award #111062), Alberta Innovates - Health Solutions, and by The Metabolomics Innovation Centre (TMIC), a nationally-funded research and core facility that supports a wide range of cutting-edge metabolomic studies. TMIC is funded by Genome Alberta, Genome British Columbia, and Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $900 million in funding from the federal government.