Toxicoepigenetics and Environmental Health: Challenges and Opportunities.

The rapidly growing field of toxicoepigenetics seeks to understand how toxicant exposures interact with the epigenome to influence disease risk. Toxicoepigenetics is a promising field of environmental health research, as integrating epigenetics into the field of toxicology will enable a more thorough evaluation of toxicant-induced disease mechanisms as well as the elucidation of the role of the epigenome as a biomarker of exposure and disease and possible mediator of exposure effects. Likewise, toxicoepigenetics will enhance our knowledge of how environmental exposures, lifestyle factors, and diet interact to influence health. Ultimately, an understanding of how the environment impacts the epigenome to cause disease may inform risk assessment, permit noninvasive biomonitoring, and provide potential opportunities for therapeutic intervention. However, the translation of research from this exciting field into benefits for human and animal health presents several challenges and opportunities. Here, we describe four significant areas in which we see opportunity to transform the field and improve human health by reducing the disease burden caused by environmental exposures. These include (1) research into the mechanistic role for epigenetic change in environment-induced disease, (2) understanding key factors influencing vulnerability to the adverse effects of environmental exposures, (3) identifying appropriate biomarkers of environmental exposures and their associated diseases, and (4) determining whether the adverse effects of environment on the epigenome and human health are reversible through pharmacologic, dietary, or behavioral interventions. We then highlight several initiatives currently underway to address these challenges.

High-Dietary Fiber Intake Alleviates Antenatal Obesity-Induced Postpartum Depression: Roles of Gut Microbiota and Microbial Metabolite Short-chain Fatty Acid Involved.

Antenatal obesity increases the risk of postpartum depression. Previous research found that dietary fiber supplementation could alleviate mental behavioral disorders. The present study aims to uncover the effects of high-dietary fiber intake on high-fat diet (HFD)-induced depressive-like behaviors and its underlying mechanism. Female C57BL6/J mice were fed with HFD to establish an antenatal obese model. A high-dietary fiber intake (inulin, 0.037 g/kcal) significantly attenuated cognitive deficits and depressive-like behaviors in the maternal mice after the offspring weaning. High-dietary fiber intake upregulated the expression of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) and suppressed neuroinflammation. Furthermore, high-dietary fiber intake restructured the gut microbiome and elevated the formation of short-chain fatty acids (SCFAs). Correlation analysis indicated that the increase in microbes such as Lactobacillus and S24-7, and SCFAs' levels were positively correlated with behavioral improvements. In conclusion, high-dietary fiber intake is a promising nutritional intervention strategy to prevent antenatal obesity-induced behavioral disorders via a microbiota-gut-brain axis.

Gut microbiota mediates intermittent-fasting alleviation of diabetes-induced cognitive impairment.

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

Protective Effects of Sesamol on Systemic Inflammation and Cognitive Impairment in Aging Mice.

Sesamol, a lignan in sesame, possesses several bioactivities, such as antioxidation, anti-inflammation, and neuroprotective capability. In this study, the effects of sesamol on aging-caused cognitive defects are investigated. Twelve-month-old mice were treated with sesamol (0.1%, w/w) as dietary supplementation for 12 weeks. Behavioral tests revealed that sesamol improved aging-associated cognitive impairments. Sesamol decreased aging-induced oxidative stress via suppression of malondialdehyde production and increased antioxidant enzymes. Histological staining showed that sesamol treatment improved aging-induced neuronal damage and synaptic dysfunction in the hippocampus. Furthermore, sesamol significantly reduced aging-induced neuroinflammation by inhibiting the microglial overactivation and inflammatory cytokine expressions. Meanwhile, the accumulation of Aß1-42 was reduced by sesamol treatment. Moreover, sesamol protected the gut barrier integrity and reduced LPS release, which was highly associated with its beneficial effects on behavioral and inflammatory changes. In conclusion, our findings indicated that the use of sesamol is feasible in the treatment of aging-related diseases.

Supplementation of Sesamin Alleviates Stress-Induced Behavioral and Psychological Disorders via Reshaping the Gut Microbiota Structure.

Sesamin, a lignan from sesame seed, has been reported to attenuate chronic mild stress-induced depressive-like behaviors. Gut microbiota play pivotal roles in mediating psychological behaviors by regulating gut barrier integrity and systemic inflammatory responses. Here, we found that oral sesamin administration (50 mg/kg·bodyweight/day) significantly attenuated depressive, aversive, repetitive, and anxiety-like behaviors in a long-term multiple nonsocial stress-treated mice model. Sesamin inhibited stress-induced gut barrier integrity damage, reduced circulating lipopolysaccharide (LPS) levels, and suppressed neuroinflammatory responses. Moreover, sesamin treatment also restructured the gut microbiome by enhancing the relative abundances of Bacteroidales and S24-7. The correlation analysis indicated that the microbiota composition changes were strongly correlated with behavioral disorders, serotonin, norepinephrine, and LPS levels. In conclusion, sesamin has preventive effects on stress-induced behavioral and psychological disorders, which might be highly related to the reshaped microbiota composition. This study provides a clue for understanding the systemic mechanism of anti-depression effects of sesamin.

Mannan Oligosaccharide Suppresses Lipid Accumulation and Appetite in Western-Diet-Induced Obese Mice Via Reshaping Gut Microbiome and Enhancing Short-Chain Fatty Acids Production.

SCOPE: Obesity is associated with gut microbiome dysbiosis. Mannose oligosaccharide (MOS) has been reported to be a potential prebiotic. The present study is aimed to determine the effects of MOS on western-diet-induced obesity and to uncover the mediating roles of the gut microbiota and microbial metabolites. METHODS AND RESULTS: Three-month-old male ICR mice are fed with a high-fat and high-fructose diet for 8 weeks. The diet-induced obese mice are then orally administrated with MOS (100 and 200 mg kg-1  d-1 ) for 4 weeks. MOS significantly reduces bodyweight gain, insulin resistance, fatty liver, and inflammatory responses in obese mice. MOS also stimulates lipolysis and inhibits lipogenesis in the adipose tissues. Moreover, MOS restructures the gut microbiome by enhancing the abundance of Bifidobacterium and Lactobacillus in obese mice. The microbial metabolite SCFAs are also increased in the feces and serum. Correlation analysis indicates that the appetite suppression and lipid-lowering effects of MOS are highly correlated with the butyrate levels. CONCLUSION: MOS suppresses the appetite, which results in less lipid deposition. The lower appetite is likely due to an altered gut microbiome and elevated SCFAs production. MOS may be a potential nutraceutical used in body weight management and gut health improvement.

Resveratrol Prevents Acrylamide-Induced Mitochondrial Dysfunction and Inflammatory Responses via Targeting Circadian Regulator Bmal1 and Cry1 in Hepatocytes.

Acrylamide, mainly formed in Maillard browning reaction during food processing, causes defects in liver circadian clock and mitochondrial function by inducing oxidative stress. Resveratrol is a polyphenol that has powerful antioxidant and anti-inflammatory activity. However, the preventive effects of resveratrol on acrylamide-triggered oxidative damage and circadian rhythm disorders are unclear at the current stage. The present research revealed that resveratrol pretreatment prevented acrylamide-induced cell death, mitochondrial dysfunction, and inflammatory responses in HepG2 liver cells. Acrylamide significantly triggered disorders of circadian genes transcription and protein expressions including Bmal1 and Cry 1 in primary hepatocytes, which were prevented by resveratrol pretreatment. Moreover, we found that the beneficial effects of resveratrol on stimulating Nrf2/NQO-1 pathway and mitochondrial respiration complex expressions in acrylamide-treated cells were Bmal1-dependent. Similarly, the inhibitory effects of resveratrol on inflammation signaling NF-κB were Cry1-dependent. In conclusion, these results demonstrated resveratrol could be a promising compound in suppressing acrylamide-induced hepatotoxicity and balancing the circadian clock.

ApoE-Dependent Protective Effects of Sesamol on High-Fat Diet-Induced Behavioral Disorders: Regulation of the Microbiome-Gut-Brain Axis.

Sesamol, an antioxidant lignan from sesame oil, possesses neuroprotective bioactivities. The present work was aimed to elucidate the systemic protective effects of sesamol on cognitive deficits and to determine the possible link between gut and brain. Wildtype and ApoE-/- mice were treated with a high-fat diet and sesamol (0.05%, w/v, in drinking water) for 10 weeks. Behavioral tests including Morris-water maze, Y-maze, and elevated plus maze tests indicated that sesamol could only improve cognitive deficits and anxiety behaviors in wildtype. Consistently, sesamol improved synapse ultrastructure and inhibited Aß accumulation in an ApoE-dependent manner. Moreover, sesamol prevented dietary-induced gut barrier damages and systemic inflammation. Sesamol also reshaped gut microbiome and improved the generation of microbial metabolites short-chain fatty acids. To summarize, this study revealed that the possible mechanism of neuroprotective effects of sesamol might be ApoE-dependent, and its beneficial effects on gut microbiota/metabolites could be translated into neurodegenerative diseases treatment.

(+)-Sesamin attenuates chronic unpredictable mild stress-induced depressive-like behaviors and memory deficits via suppression of neuroinflammation.

Depression is a mood disorder that is related to neuroinflammation and cognition loss. This study is aimed to determine the potential antidepressant effects of (+)-sesamin, a lignan component of sesame, in a mild stress-induced depression mouse model. CD-1 mice were treated with chronic unpredictable mild stress (CUMS) process and orally administrated with sesamin (50 mg/kg/d) for 6 weeks. Behavioral tests including forced swimming test, tail suspension test, open field test, and elevated plus maze test demonstrated that sesamin treatment inhibited CUMS-induced mice depressant-like behaviors and anxiety, without changing immobility. It was found that sesamin prevented stress-induced decease levels of 5-HT and NE in striatum and serum. Cognitive deficits were assessed using Y-maze and Morris water maze test. Sesamin treatment also prevented stressed-induced memory impairments and neuronal damages. Consistently, sesamin also enhanced synapse ultrastructure and improved expressions of PSD-95 in stressed mice hippocampus with improving neurotrophic factors expression including BDNF and NT3. Moreover, sesamin treatment significantly prevented CUMS-induced neuroinflammation by inhibiting over-activation of microglia and expressions of inflammatory mediators including iNOS, COX-2, TNF-α and IL-1ß in stressed mice hippocampus and cortex. These results illustrated that sesamin markedly improved CUMS-induced depression and memory loss via inhibiting neuroinflammation, which indicate that as food component, sesamin might be also a novel potential therapeutic for depression.

Retinal nerve fiber layer thickness changes in Schizophrenia: A meta-analysis of case-control studies.

Studies using optical coherence tomography (OCT) to compare retinal nerve fiber layer thickness in subjects with schizophrenia and healthy controls have yielded inconsistent results. We aimed to compare changes in retinal nerve fiber layer thickness in schizophrenia and healthy controls via a meta-analysis. Relevant studies were selected via an electronic search of the Cochrane Controlled Trials Register, Pubmed, and Embase. All included studies measured average and 4-quadrant (temporal, superior, nasal, and inferior) retinal nerve fiber layer thickness via OCT. Statistical analysis was performed using RevMan 5.0 software. Seven case-control studies involving collective totals of 245 eyes in patients with schizophrenia and 220 eyes in healthy controls were ultimately included in this meta-analysis. Statistical analysis revealed that average retinal nerve fiber layer thickness in patients with schizophrenia was significantly reduced compared to that of healthy controls. Additionally, retinal nerve fiber layer thickness in the inferior quadrant, nasal quadrant, and temporal quadrant differed significantly between the two groups, while differences in the superior quadrant did not. In view of these results, we suggest that peripapillary retinal nerve fiber layer thickness as measured by OCT may be a useful tool for the diagnosis of schizophrenia.

Effect of Methyl-CpG binding domain protein 2 (MBD2) on AMD-like lesions in ApoE-deficient mice.

The role of methyl-CpG binding domain protein 2 (MBD2) in an ApoE-deficient mouse model of age-related macular degeneration (AMD) was investigated. Eight-week-old Mbd2/ApoE double deficient (Mbd2(-/-) ApoE(-/-)) mice (n=12, 24 eyes, experimental group) and MBD2 (wt) ApoE(-/-) mice (n=12, 24 eyes, control group) were fed on Western-type diet for 4 months. The mice were sacrificed, and total serum cholesterol levels were analyzed and Bruch's membrane (BM) of the eyes was removed for ultrastructural observation by transmission electron microscopy. Moreover, intercellular adhesion molecule 1 (ICAM-1) immunoreactivities were evaluated by fluorescence microscopy in sections of the eyes in both groups for further understanding the function mechanism of MBD2. There was no significant difference in the total serum cholesterol levels between control group and experimental group (P>0.05). Transmission electron microscopy revealed that AMD-like lesions, various vacuoles accumulated on BM, notable outer collagenous layer deposits and dilated basal infoldings of retinal pigment epithelium (RPE) were seen in both groups, and the BM in control group was significantly thickened as compared with experimental group (P<0.05). Fluorescence micrographs exhibited the expression of ICAM-1 in choroid was higher in control group than in experimental group. We are led to conclude that MBD2 gene knockout may lead to accumulation of more deposits on the BM and influence the pathogenesis of AMD via triggering endothelial activation and inflammatory response in choroid, improving microcirculation, and reducing lipid deposition so as to inhibit the development of AMD-like lesions. Our study helps to provide a new therapeutic approach for the clinical treatment of AMD.

The Ubiquitin Proteasome Pathway (UPP) in the regulation of cell cycle control and DNA damage repair and its implication in tumorigenesis.

Accumulated evidence supports that the ubiquitin proteasome pathway (UPP) plays a crucial role in protein metabolism implicated in the regulation of many biological processes such as cell cycle control, DNA damage response, apoptosis, and so on. Therefore, alterations for the ubiquitin proteasome signaling or functional impairments for the ubiquitin proteasome components are involved in the etiology of many diseases, particularly in cancer development. In this minireview, we first give a brief outline for the ubiquitin proteasome pathway, we then discuss with focus for the ubiquitin proteasome pathway in the regulation of cell cycle control and DNA damage response, the relevance for the altered regulation of these signaling pathways in tumorigenesis is also reviewed. We finally assess and summarize the advancement for targeting the ubiquitin proteasome pathway in cancer therapy. A better understanding of the biological functions underlying ubiquitin regulatory mechanisms would provide us a wider prospective on cancer treatment.