Review on novel toxicological effects and personalized health hazard in workers exposed to low doses of benzene.

Several recent reports indicate health hazards for workers with below occupational limit exposure to benzene (BZ). Our updated review indicates that such low exposures induced traditional as well as novel toxicity/genotoxicity, e.g., increased mitochondria copy numbers, prolongation of telomeres, impairment of DNA damage repair response (DDRR), perturbations of expression in non-coding RNAs, and epigenetic changes. These abnormalities were associated with alterations of gene expression and cellular signaling pathways which affected hematopoietic cell development, expression of apoptosis, autophagy, etc. The overarching mechanisms for induction of health risk are impaired DDRR, inhibition of tumor suppressor genes, and changes of MDM2-p53 axis activities that contribute to perturbed control for cancer pathways. Evaluation of the unusual dose-responses to BZ exposure indicates cellular over-compensation and reprogramming to overcome toxicity and to promote survival. However, these abnormal mechanisms also promote the induction of leukemia. Further investigations indicate that the current exposure limits for workers to BZ are unacceptable. Based on these studies, the new exposure limits should be less than 0.07 ppm rather than the current 1 ppm. This review also emphasizes the need to conduct appropriate bioassays, and to provide more reliable decisions on health hazards as well as on exposure limits for workers. In addition, it is important to use scientific data to provide significantly improved risk assessment, i.e., shifting from a population- to an individual-based risk assessment.

From inequitable to sustainable e-waste processing for reduction of impact on human health and the environment.

Recycling of electric and electronic waste products (e-waste) which amounted to more than 50 million metric tonnes per year worldwide is a massive and global operation. Unfortunately, an estimated 70-80% of this waste has not been properly managed because the waste went from developed to low-income countries to be dumped into landfills or informally recycled. Such recycling has been carried out either directly on landfill sites or in small, often family-run recycling shops without much regulations or oversights. The process traditionally involved manual dismantling, cleaning with hazardous solvents, burning and melting on open fires, etc., which would generate a variety of toxic substances and exposure/hazards to applicators, family members, proximate residents and the environment. The situation clearly calls for global responsibility to reduce the impact on human health and the environment, especially in developing countries where poor residents have been shouldering the hazardous burden. On the other hand, formal e-waste recycling has been mainly conducted in small scales in industrialized countries. Whether the latter process would impose less risk to populations and environment has not been determined yet. Therefore, the main objectives of this review are: 1. to address current trends and emerging threats of not only informal but also formal e-waste management practices, and 2. to propose adequate measures and interventions. A major recommendation is to conduct independent surveillance of compliance with e-waste trading and processing according to the Basel Ban Amendment. The recycling industry needs to be carefully evaluated by joint effort from international agencies, producing industries and other stakeholders to develop better processes. Subsequent transition to more sustainable and equitable e-waste management solutions should result in more effective use of natural resources, and in prevention of adverse effects on health and the environment.

Challenge-comet assay, a functional and genomic biomarker for precision risk assessment and disease prevention among exposed workers.

Advancements in genomic technologies have ushered application of innovative changes into biomedical sciences and clinical medicine. Consequently, these changes have created enormous opportunities to implement precision population/occupational disease prevention and target-specific disease intervention (or personalized medicine). To capture the opportunities, however, it is necessary is to develop novel, especially genomic-based, biomarkers which can provide precise and individualized health risk assessment. In this review, development of the Challenge-comet assay is used as an example to demonstrate how assays need to be validated for its sensitivity, specificity, and functional and quantitative features, and how assays can be used to provide individualized health risk assessment for precision prevention and intervention. Other examples of genomic-based novel biomarkers will also be discussed. Furthermore, no biomarkers can be used alone therefore their integrated usage with other biomarkers and with personal data bases will be discussed.

Associations between functional polychlorinated biphenyls in adipose tissues and prognostic biomarkers of breast cancer patients.

BACKGROUND: Exposure to polychlorinated biphenyls (PCBs) has been shown to influence expression of some biomarkers that are predictive/prognostic for breast cancer. Therefore, our study was conducted to further investigating associations of different functional PCBs in adipose tissue with breast cancer prognostic biomarkers. METHODS: Two hundred and five breast cancer patients were recruited in Shantou, China. Breast adipose tissues were collected during their resection surgery and levels of 7 PCB congeners were analyzed by gas chromatography-mass spectrometry (GC-MS). The PCB congeners were divided into 4 groups according to structure-activity. Socio-demographic, clinical and pathological information were obtained from questionnaire and digital medical records. Odds ratios (ORs) for associations between prognostic biomarkers and PCB levels (tertile 3 [T3], tertile 2 [T2] vs. tertile 1) were estimated from logistic regression models. RESULTS: Most PCB congeners were detectable, with a highest level (22.06 ng/g lipid) of PCB153. As for estrogenic PCBs, increased PCB52 exposure was positively associated with PR expression (ORT2 = 2.36, Ptrend = 0.054), but higher PCB101 level was negatively associated with HER-2 (ORT3 = 0.24, Ptrend = 0.029) and tumor size (OR = 0.43). Limited dioxin-like PCB138 exposure was positively associated with ER (ORT2 = 3.23, ORT3 = 3.77, Ptrend = 0.047) but negatively with Top-IIα expression (ORT2 = 0.35, ORT3 = 0.28, Ptrend = 0.080). Higher PCB153 (CYP inducer) level was negatively associated with ER (ORT2 = 0.32, ORT3 = 0.19, Ptrend = 0.038) but positively with Ki-67 expression (ORT2 = 1.43, ORT3 = 3.60, Ptrend = 0.055). Higher neurotoxic PCB28 was positively associated with HER-2 (ORT3 = 5.43, Ptrend = 0.006) and tumor size (OR = 2.37). Moreover, total PCBs exposure was positively associated with VEGF-C (ORT2 = 76.91, ORT3 = 97.96, Ptrend = 0.041) and tumor metastasis (OR = 2.25). CONCLUSIONS: Different functional PCB congeners have different associations (both positive and negative) with breast cancer prognostic biomarkers, as well as tumor classification stage. Therefore, the development and aggressiveness of breast cancer may depend upon exposure to specific structure-activity of PCBs.

Exposure to perfluorooctane sulfonate based on circadian rhythm changes the fecundity and expression of certain genes on the hypothalamic-pituitary-gonadal-liver axis of female zebrafish.

Exposure of a variety of experimental animals to perfluorooctane sulfonate (PFOS) has shown that it is a potent endocrine-disrupting chemical. However, its interaction with the circadian rhythm on responses along the hypothalamic - pituitary - gonadal - liver (HPGL) axis should be of significant value but has not been adequately investigated. In present study, the effects of PFOS on fecundity, levels of estradiol (E2) and expression of certain genes on the HPGL axis at two time points (8:00 AM and 7:00 PM) were compared after female zebrafish were exposed to 0, 2, 20 and 200 µg/L PFOS for 21 days. In brain, expressions of gonadotropin-releasing hormone (GnRH), gonadotropin-releasing hormone receptor (GnRHr), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were significantly different after the exposure when sampled at 8:00 AM and at 7:00 PM (P < .05). In liver, significant down-regulation of vitellogenin1 (VTG1) and estrogenic receptor α (ERα) were observed at 7:00 PM compared with 8:00 AM (P < .05). In ovary, the level of CYP19 was significantly different at the two time points (P < .05). The increase of E2 after exposure to 20 µg/L PFOS at 8:00 AM caused compensatory down-regulation of GnRHr and up-regulation of VTG1 and ERα, but not at 7:00 PM. Profiles of concentrations of E2 and several gene expressions alongside the HPGL axis were different between two times points. The change of E2 and gene expressions were more perturbed by PFOS at 8:00 AM than at 7:00 PM with circadian rhythm.

Innovative Application of a Home-Based and Remote Sensing Cardiac Rehabilitation Protocol in Chinese Patients After Percutaneous Coronary Intervention.

BACKGROUND: Medical care for the Chinese population has been focused on first-line activities, that is, therapy, but with little follow-up on treated patients. However, efficacy of therapy is highly dependent upon post-therapy recovery. For coronary heart disease (CHD), home-based cardiac telerehabilitation (HBCTR) is an alternative to hospital-based or center-based cardiac rehabilitation, and is an innovative approach to enhance recovery, but the approach is seldom used in China. Our preliminary survey in Shantou, China, indicated that most CHD patients showed a positive attitude toward the HBCTR technology. Our follow-up study was focused on assessing the effect of the HBCTR program in low-risk patients after percutaneous coronary intervention (PCI). MATERIALS AND METHODS: A two-arm randomized controlled trial was conducted at the First Affiliated Hospital of the Shantou University Medical College, China. The effectiveness of this program was measured by using blood pressure, Six-Minute Walking Test (6MWT), Fagerstrom Test for Nicotine Dependence (FTND), Cardiac Depression Scale (CDS), and SF-36 Health Survey (SF36). RESULTS: A total of 80 post-PCI patients were recruited and randomly divided into two equal groups. Based upon our effort, the usual care (UC) group received paper-based CHD educational booklets and biweekly outpatient review. The HBCTR group carried out outdoor walking/jogging exercise with real-time physiological monitoring along with CHD education materials. After the 6-week intervention, the 6MWT, SF36 (PCS, MCS), FTND and CDS in both groups were found to have significantly improved compared with baseline. In addition, the improvements in SF36, FTND scores, and 6MWT distance in the HBCTR group were significantly better than those in the UC group (p < 0.05). CONCLUSION: Our observations indicated that the HBCTR program may be applied successfully in Chinese patients who had very little technical skills and its application may be highly cost-effective.

Cigarette smoking in China: public health, science, and policy.

Throughout the world, cigarette smoking is a habit that causes serious health, economic, and social problems. Therefore, many countries have taken an active role to control and to ban smoking. The chronic smoking problem in China is particularly acute because China has the largest population of smokers in the world, over 300 million currently. If 30% of these smokers were to die of smoke-related diseases in the next 20 years, the impact from the more than 90 million premature deaths could be damaging to China. In addition, numerous non-smokers also experience health problems from exposure to environmental tobacco smoke. China's efforts to reduce or to ban smoking in certain public places have not been well-coordinated or enforced compared with those in other countries. Therefore, success has been minimal. Consequently, leaders in China should not be complacent about combating the serious national health problem. A multiprong approach in combination with the MPOWER policy from the World Health Organization that targets different levels of acquisition of the smoking habit must be used. Examples may include the government's reduced reliance on profits from the sale of cigarettes, the elimination of advertisements that encourage smoking among young individuals, the presentation of more graphic illustration of harmful effects from smoking on every pack of cigarettes, higher taxes/prices on cigarettes, and the implementation of enforceable bans on smoking in public places. As shown in other countries, such coordinated effort can be highly effective in the reduction of smoking and can have healthy consequences.

Lymphocyte-based challenge DNA-repair assays for personalized health risk assessment.

Combinations of genetic and environmental factors are responsible for the development of many human diseases, such as cancer, as demonstrated using various biomarkers. Within this scenario, DNA repair holds a gate-keeper position which determines outcomes after appearance of DNA damage and, therefore, adverse cellular consequences, e.g., initiation of carcinogenesis. DNA repair deficiency and some of the subsequent events can be validated from studies using live cells from cancer patients. However, these deficiencies/events are difficult to demonstrate in live cells from normal individuals because individual variations in DNA repair capacities (DRC) are too low to be measured easily. Such lack of information has been hindering progress in developing personalized disease prevention and intervention protocols, especially among exposed populations. However, using a variety of challenge assays as biomarkers, variations in individual's DRC can be amplified in live cells and be determined. Furthermore, evidence indicates that DRC are not only inherited but can also be modified by environmental factors (e.g., nutritional status and exposure to genotoxic substances). Using these challenge assays, e.g., in live lymphocytes, individual's DRC can be holistically and functionally determined as well as quantitated. With the more precise information, assessment of health risk can be better determined on an individual rather than on a population basis. This review provides a succinct summary on the development and application of recent challenge assays in lymphocytes which can provide measurements of individuals' DRC, and on the latest data for more precise disease prevention and intervention.

Impact of environmental chemicals on craniofacial skeletal development: Insights from investigations using zebrafish embryos.

Craniofacial skeletal anomalies are among the most common structural birth defects around the world. Various studies using human populations and experimental animals have shown that genetic and environmental factors play significant roles in the causation and progression of these anomalies. Environmental factors, such as teratogens and toxin mixtures, induce craniofacial anomalies are gaining heightened attention. Among experimental investigations, the use of the zebrafish (Danio rerio) has been increasing. A major reason for the increased use is that the zebrafish boast a simple craniofacial structure, and facial morphogenesis is readily observed due to external fertilization and transparent embryo, making it a valuable platform to screen and identify environmental factors involved in the etiology of craniofacial skeletal malformation. This review provides an update on harmful effects from exposure to environmental chemicals, involving metallic elements, nanoparticles, persistent organic pollutants, pesticides and pharmaceutical formulations on craniofacial skeletal development in zebrafish embryos. The collected data provide a better understanding for induction of craniofacial skeletal anomalies and for development of better prevention strategies.

The Interactive Effects of Cognition on Coping Styles among Chinese during the COVID-19 Pandemic.

BACKGROUND: The outbreak of Coronavirus Disease 2019 (COVID-19) has seriously affected people's life. The main aim of our investigation was to determine the interactive effects of disease awareness on coping style among Chinese residents during the COVID-19 pandemic. METHODS: A total of 616 Chinese residents from 28 provinces were recruited to participate in this investigation. A questionnaire was used to collect demographic characteristics, cognition of COVID-19, and disease-related stress sources. Coping styles were assessed via the Simplified Coping Style Questionnaire (SCSQ). RESULTS: The survey showed that the main source of information on COVID-19 was different in relation to gender, age, educational level, and occupation (p < 0.001). People's knowledge of the disease, preventive measures, and stress factors were different in relation to demographic characteristics (p < 0.001). Compared with the baseline values, the scores of positive coping and negative coping based on SCSQ in relation to gender, age, educational level, and occupation were statistically significant (p < 0.001, except for participants older than 60 years). Different educational levels corresponded to statistical significant differences in positive coping (p = 0.004) but not in negative coping. CONCLUSIONS: During the pandemic, people with different characteristics had different levels of preventive measures' awareness, which influenced their coping styles. Therefore, during public health emergencies, knowledge of prevention and control measures should be efficiently provided to allow more effective coping styles.

Occupational Health Risk Assessment of Benzene, Toluene, and Xylene in Shanghai.

OBJECTIVE: This study was designed to conduct a retrospective and systematic occupational health risk assessment (OHRA) of enterprises that used benzene, toluene, and xylene (BTX) in Shanghai, China. METHODS: All data for the study were obtained from 1,705 occupational health examination and evaluation reports from 2013 to 2017, and a semiquantitative model following Chinese OHRA guidelines (GBZ/T 298-2017) was applied for the assessment. RESULTS: The selected enterprises using BTX were mainly involved in manufacturing of products. Using the exposure level method, health risk levels associated with exposure to BTX were classified as medium, negligible, or low. However, the risk levels associated with benzene and toluene were significantly different according to job types, with gluers and inkers exhibiting greater health risks. For the same job type, the health risk levels assessed using the comprehensive index method were higher than those using the exposure level method. CONCLUSION: Our OHRA reveals that workers who are exposed to BTX still face excessive health risk. Additionally, the risk level varied depending on job categories and exposure to specific chemicals. Therefore, additional control measures recommended by OHRA guidelines are essential to reduce worker exposure levels.

Changes in miR-222 expression, DNA repair capacity, and MDM2-p53 axis in association with low-dose benzene genotoxicity and hematotoxicity.

Mechanisms for hematotoxicity and health effects from exposure to low doses of benzene (BZ) remain to be identified. To address the information gap, our investigation was focused onto using appropriate populations and cell cultures to investigate novel BZ-induced effects such as disruption of DNA repair capacity (DRC). From our study, abnormal miRNAs were identified and validated using lymphocytes from 56 BZ-poisoned workers and 53 controls. In addition, 173 current BZ-exposed workers and 58 controls were investigated for key miRNA expression using RT-PCR and for cellular DRC using a challenge assay. Subsequently, the observed activities in lymphocytes were verified using human HL-60 (p53 null) and TK6 (p53 wild-type) cells via 1,4-benzoquinone (1,4-BQ) treatment and miR-222 interferences. The targeting of MDM2 by miR-222 was validated using a luciferase reporter. Our results indicate induction of genotoxicity in lymphocytes from workers with low exposure doses to BZ. In addition, miR-222 expression was up-regulated among both BZ-poisoned and BZ-exposed workers together with inverse association with DRC. Our in vitro validation studies using both cell lines indicate that 1,4-BQ exposure increased expression of miR-222 and Comet tail length but decreased DRC. Loss of miR-222 reduced DNA damage, but induced S-phase arrest and apoptosis. However, silencing of MDM2 failed to activate p53 in TK6 cells. In conclusion, our in vivo observations were confirmed by in vitro studies showing that BZ/1,4-BQ exposures caused genotoxicity and high expression of miR-222 which obstructed expression of the MDM2-p53 axis that led to failed activation of p53, abnormal DRC and serious biological consequences.

Lead affects apoptosis and related gene XIAP and Smac expression in the hippocampus of developing rats.

Lead (Pb) exposure poses devastating effects on central nervous system development of children. To replicate aspects of this neurotoxicity, we examined the effect of lead on the expression of apoptosis and of apoptosis-related genes, XIAP (X chromosome-linked inhibitor of apoptosis protein) and Smac (second mitochondrial activator of caspase), in the hippocampus of developing rats. A total of 48 rats (30-day old) were randomly divided into four groups for intragastrical perfusion of lead acetate [Pb(Ac)2]: untreated, low (2 mg/kg/d), medium (20 mg/kg/d), and high (200 mg/kg/d) dose groups. Pb content was determined in blood, and the apoptosis indexes and XIAP and Smac gene expression were analyzed in the hippocampus. There was a significant difference in apoptosis indexes (AI) between the exposed and control groups (p < 0.01). AI was highest in the high exposure group. XIAP gene expression was reduced in the exposed groups and the expression was negatively correlated with blood lead levels (BLLs) (p < 0.05). But the four groups did not differ in the expression of Smac (p > 0.05). Our data indicate that exposure to Pb(Ac)2 caused a dose-dependent and significant increase of apoptosis in the hippocampus of developing rats through depressing the expression of the XIAP but not the Smac genes.

Public health issues from crude-oil production in the Ecuadorian Amazon territories.

Crude oil production (COP) is a high-pollution industry but the vast Amazon rainforest has been an active COP zone for South America. Although COP has been associated with a variety of health effects among workers around the world, such effects have not been adequately investigated in the Amazon region, especially at the community level. Therefore, this review was conducted to provide a report about COP in the Amazon of Ecuador and about its association with health status of indigenous human populations. Some epidemiological surveys in the Amazonian Territories indicate that COP has been associated with health problems in the surrounding populations, e.g. cancers in the stomach, rectum, skin, soft tissue, kidney and cervix in adults, and leukemia in children. In addition, some biomarkers and mechanistic studies show exposure effects. However, due to limitations from these studies, contradictory associations have been reported. Our review indicates that COP in the Amazonian territories of northern Ecuador was characterised by contamination which could have affected the indigenous and non-indigenous populations. However, there have not been dedicated investigations to provide relationships between the contamination and the subsequent exposure-health effects. Since indigenous populations have different lifestyle and cultures from regular city dwellers, systematic studies on their potential health hazards need to be conducted. Due to the remote locations and sparse populations, these new studies may involve the use of novel and genomic-based biomarkers as well as using high technology in the remote regions.

Effects of Micronucleus Frequencies and Mitochondrial DNA Copy Numbers among Benzene-Exposed Workers in China.

To provide a more comprehensive understanding of genotoxic effects from benzene exposure, its effects on induction of mitochondrial DNA copy number (MtDNAcn) and of micronucleus (MN) were investigated using peripheral blood from workers in China. Changes in mtDNAcn and MN were determined using quantitative real-time polymerase chain reaction (PCR) and cytokinesis-block micronucleus assays (CBMN), respectively, in 58 control and 174 benzene-exposed workers in Shanghai, China. Among the exposed workers, relative mtDNAcn increased and then decreased with increasing doses of benzene exposure. Significant and dose-dependent increase in MN frequencies were observed among the different exposure groups. In addition, the relative mtDNAcn were significantly associated with the MN frequencies in the low-level exposure group (P = 0.046), but not in the high dose groups. Therefore, the mechanisms for induction of MtDNAcn and MN by benzene may be similar from exposure to low doses but different from high doses. Similar increase of MN frequencies and MtDNAcn may be due to oxidative stress induced by benzene at low concentrations, while higher concentrations may start to initiate the cell death pathway. The pathway may be associated with excessive MtDNAcn which can initiate apoptosis while MN can continue to be induced. However, the differential mechanisms need to be investigated because they may represent different levels of risk for different health consequences. On the other hand, our data indicate that induction of MtDNAcn may be a sensitive genotoxic biomarker for workers with exposure to low dose of benzene. Environ. Mol. Mutagen. 61:355-360, 2020. © 2020 Wiley Periodicals, Inc.

Biomarkers in population studies: environmental mutagenesis and risk for cancer.

Biomarkers of exposure and biological effects have frequently been used to monitor populations for their exposure to toxic substances and for the prediction of disease risk, such as cancer. Current interest is focused on improving the use of biomarkers to better understand biological mechanisms for improved risk assessment. Such improvements involve the understanding of inter-individual variations in response to exposure, integration of genomic and proteomic technologies into biomarker studies, development of functional biomarkers, and the use of high tech procedures like biosensors and lab-on-a-chip approaches. The latter two approaches can provide unique contributions by providing specific and real-time reporting of excessive exposure. Based on the generation of more reliable information regarding exposure-specific effects, biological mechanisms, and health risk, more realistic prevention and intervention protocols have been implemented. The usefulness and application of these biomarkers and technologies will be presented.

Correction to: Involvement of gut microbiome in human health and disease: brief overview, knowledge gaps and research opportunities.

[This corrects the article DOI: 10.1186/s13099-018-0230-4.].

Abrogation of estrogen receptor signaling augments cytotoxicity of anticancer drugs on CaSki cervical cancer cells.

BACKGROUND: We have reported that a gene therapy approach, using a dominant-negative estrogen receptor blocker (DN) gene, can cause cell death in cervical cancer cells in vitro. We investigated the mechanisms for enhanced cell killing when DN was combined with cisplatin (CP) and paclitaxel (TX). MATERIALS AND METHODS: Cells were transduced with DN at 24 h and/or treated with drugs at 48 h, and harvested at 48 and 72 h after transduction. Effects were determined using the MTT cytotoxic, and TUNEL and caspase-3 activity apoptotic assays. RESULTS: Each agent induced cytotoxic and apoptotic effects, and activated caspase-3. In the combined treatments, significant synergistic effects were observed based on the MTT and TUNEL assays, but with antagonistic caspase-3 activation effect. CONCLUSION: The enhanced cell killing effect was mediated by the initiation of new and multiple mechanisms, particularly via caspase-independent pathways.

Vth International Conference on Environmental Mutagens in Human Populations: introduction.

The Vth International Conference on Environmental Mutagens in Human Populations (VthICEMHP), 20-24 May 2007 was successfully completed in Antalya, Turkey. With approximately 200 participants from 35 countries, the conference participants enjoyed extensive exchange of scientific and cultural expertise. Like the previous conferences in this series, collaborative and sustainable projects were developed among the participants. Publications in this monograph represent outstanding reviews and experimental data from invited speakers.

Involvement of gut microbiome in human health and disease: brief overview, knowledge gaps and research opportunities.

The commensal, symbiotic, and pathogenic microbial community which resides inside our body and on our skin (the human microbiome) can perturb host energy metabolism and immunity, and thus significantly influence development of a variety of human diseases. Therefore, the field has attracted unprecedented attention in the last decade. Although a large amount of data has been generated, there are still many unanswered questions and no universal agreements on how microbiome affects human health have been agreed upon. Consequently, this review was written to provide an updated overview of the rapidly expanding field, with a focus on revealing knowledge gaps and research opportunities. Specifically, the review covered animal physiology, optimal microbiome standard, health intervention by manipulating microbiome, knowledge base building by text mining, microbiota community structure and its implications in human diseases and health monitoring by analyzing microbiome in the blood. The review should enhance interest in conducting novel microbiota investigations that will further improve health and therapy.