The use of psychostimulants and alcohol disrupts blood-brain barrier (BBB) integrity, resulting in alterations to cellular function, and contributes to neurotoxicity. The BBB is the critical boundary of the central nervous system (CNS) where it maintains intracellular homeostasis and facilitates communication with the peripheral circulation. The BBB is regulated by tight junction (TJ) proteins that closely interact with endothelial cells (EC). The complex TJ protein network consists of transmembrane proteins, including claudins, occludins, and junction adhesion molecules (JAM), as well as cytoskeleton connected scaffolding proteins, zonula occludentes (ZO-1, 2, and 3). The use of psychostimulants and alcohol is known to affect the CNS and is implicated in various neurological disorders through neurotoxicity that partly results from increased BBB permeability. The present mini review primarily focuses on BBB structure and permeability. Moreover, we assess TJ protein and cytoskeletal changes induced by cocaine, methamphetamine, morphine, heroin, nicotine, and alcohol. These changes promote glial activation, enzyme potentiation, and BBB remodeling, which affect neuroinflammatory pathways. Although the effect of drugs of abuse on BBB integrity and the underlying mechanisms are well studied, the present review enhances the understanding of the underlying mechanisms through which substance abuse disorders cause BBB dysfunction.
We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors.
The overwhelming increase in the global incidence of obesity and its associated complications such as insulin resistance, atherosclerosis, pulmonary disease, and degenerative disorders including dementia constitutes a serious public health problem. The Inhibitor of DNA Binding/Differentiation-3 (ID3), a member of the ID family of transcriptional regulators, has been shown to play a role in adipogenesis and therefore ID3 may influence obesity and metabolic health in response to environmental factors. This review will highlight the current understanding of how ID3 may contribute to complex chronic diseases via metabolic perturbations. Based on the increasing number of reports that suggest chronic exposure to and accumulation of endocrine disrupting chemicals (EDCs) within the human body are associated with metabolic disorders, we will also consider the impact of these chemicals on ID3. Improved understanding of the ID3 pathways by which exposure to EDCs can potentiate complex chronic diseases in populations with metabolic disorders (obesity, metabolic syndrome, and glucose intolerance) will likely provide useful knowledge in the prevention and control of complex chronic diseases associated with exposure to environmental pollutants.
Human immunodeficiency virus (HIV) infection and the psychostimulant drug cocaine are known to induce epigenetic changes in DNA methylation that are linked with the severity of viral replication and disease progression, which impair neuronal functions. Increasing evidence suggests that changes in DNA methylation and hydroxymethylation occur in mitochondrial DNA (mtDNA) and represent mitochondrial genome epigenetic modifications (mitoepigenetic modifications). These modifications likely regulate both mtDNA replication and gene expression. However, mtDNA methylation has not been studied extensively in the contexts of cocaine abuse and HIV-1 infection. In the present study, epigenetic factors changed the levels of the DNA methyltransferases (DNMTs) DNMT1, DNMT3a, and DNMT3b, the Ten-eleven translocation (TET) enzymes 1, 2, and 3, and mitochondrial DNMTs (mtDNMTs) both in vitro and in vivo. These changes resulted in alterations in mtDNA methylation levels at CpG and non-CpG sites in human primary astrocytes as measured using targeted next-generation bisulphite sequencing (TNGBS). Moreover, mitochondrial methylation levels in the MT-RNR1, MT-ND5, MT-ND1, D-loop and MT-CYB regions of mtDNA were lower in the HIV-1 Tat and cocaine treatment groups than in the control group. In summary, the present findings suggest that mitoepigenetic modification in the human brain causes the mitochondrial dysfunction that gives rise to neuro-AIDS.
The rising global incidence of obesity cannot be fully explained within the context of traditional risk factors such as an unhealthy diet, physical inactivity, aging, or genetics. Adipose tissue is an endocrine as well as a metabolic organ that may be susceptible to disruption by environmental estrogenic chemicals. Since some of the endocrine disruptors are lipophilic chemicals with long half-lives, they tend to bioaccumulate in the adipose tissue of exposed populations. Elevated exposure to these chemicals may predispose susceptible individuals to weight gain by increasing the number and size of fat cells. Genetic studies have demonstrated that the transcriptional regulator inhibitor of differentiation-3 (ID3) promotes high fat diet-induced obesity in vivo. We have shown previously that PCB153 and natural estrogen 17β-estradiol increase ID3 expression. Based on our findings, we postulate that ID3 is a molecular target of estrogenic endocrine disruptors (EEDs) in the adipose tissue and a better understanding of this relationship may help to explain how EEDs can lead to the transcriptional programming of deviant fat cells. This review will discuss the current understanding of ID3 in excess fat accumulation and the potential for EEDs to influence susceptibility to obesity or metabolic disorders via ID3 signaling.
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