Advances and perspectives in environmental health research in China

Environmental health research aims to identify environmental conditions suitable for the healthy living and reproduction of human beings.Through the interdisciplinary research bridging environmental sciences and health/medical sciences,the impacts of physical,chemical,and biological environmental factors on human health are investigated.This includes identifying environmental factors detrimental to human health,evaluating human exposure characteristics to environmental factors,clarifying causal relationships between environmental exposure and health effects,analyzing the underlying biochemical mechanisms,linking environmental factors to the onset and progression of diseases,establishing exposure-response relationships,and determining effect thresholds.Ultimately,the results of environmental health research can serve as a scientific basis for formulating environmental management strategies and guiding prevention and intervention measures at both the public and individual levels.This paper summarizes the recent advances and future perspectives of environmental health research in China,as reported by a group of Chinese scientists who recently attended a workshop in Hainan,China.While it is not intended to provide a comprehensive review of this expansive field,it offers a glimpse into the significant progress made in understanding the health impacts of environmental factors over the past decade.Looking ahead,it is imperative not only to sustain efforts in studying the health effects of traditional environmental pollution,but also to prioritize research on the health impacts of emerging pollutants and climate change.

Maternal Bisphenol B Exposure and Mammary Gland Development of Offspring:A Time-Series Analysis

Breast cancer incidence has increased and become the world’s most prevalent cancer,which is related to abnormal development of mammary glands and thought to be influenced by environment endocrine disruptors such as bisphenol A(BPA).However,whether its substitution,bisphenol B(BPB),has similar effects remains a concern.In the present study,a maternal exposure model of ICR mice combined time-series RNA-seq analysis was established to explore the underlying correlation among maternal BPB exposure(300μg/kg body weight),mammary gland development,and long-term breast health in offspring.The results showed that BPB exposure disrupted hormonal homeostasis of the female offspring but did not affect the branch development of mammary glands in a time-dependent manner.However,at postnatal day 90(PND90),BPB exposure resulted in duct dilatation,lobular hyperplasia,and inflammatory cell infiltration and increased the number of hormone receptor-expressing(HR+)luminal cells in offspring.Further,the differentially expressed genes in time-series analysis of RNA-seq for mammary glands of the female offspring were enriched in the morphogenesis of branching structures,branching epithelium,and branching morphogenesis of epithelial tubes,which are always considered gland development.Interestingly,the results of RNA-seq also suggested that progesterone receptor(Pgr)mRNA expression in the BPB group was elevated at PND90,and breast cancer related genes such as GATA binding protein 3(Gata3)and epidermal growth factor receptor(Egfr)were also altered.These findings suggested that maternal BPB exposure did not accelerate mammary gland development or lead to obvious morphological anomalies of offspring,but it induced pathological changes and altered cancer related gene expression in adult offspring breast.

Cardiac energy metabolism disorder mediated by energy substrate imbalance and mitochondrial damage upon tebuconazole exposure

Tebuconazole exposure has been described as an increasing hazard to human health.An increasing number of recent studies have shown a positive association between tebuconazole exposure and cardiovascular disease risk,which is characterized by the reduction of adenosine triphosphate(ATP)synthesis.However,researches on the damage of tebuconazole exposure to energy metabolism and the related molecular mechanisms are limited.In the present study,male C57BL/6 mice were treated with tebuconazole at different low concentrations for 4 weeks.The results indicated that tebuconazole could accumulate in the heart and further induce the decrease of ATP content in the mouse heart.Importantly,tebuconazole induced an obvious shift in substrate utilization of fatty acid and glucose by disrupting their corresponding transporters(GLUT1,GLUT4,CD36,FABP3 and FATP1)expression,and significantly repressed the expression of mitochondrial biogenesis(Gabpa and Tfam)and oxidative phosphorylation(CS,Ndufa4,Sdhb,Cox5a and Atp5b)related genes in a dosedependent manner.Further investigation revealed that these alterations were related to the IRS1/AKT and PPARγ/RXRαpathways.These findings contribute to a better understanding of triazole fungicide-induced cardiovascular disease by revealing the key indicators associated with this phenomenon.

Perfluorinated iodine alkanes promote the differentiation of mouse embryonic stem cells by regulating estrogen receptor signaling

Investigating the development toxicity of perfuorinated iodine alkanes(PFIs)is critical,given their estrogenic effects through binding with estrogen receptors(ERs).In the present study,two PFIs,including dodecafuoro-1,6-diiodohexane(PFHx DI)and tridecafuorohexyl iodide(PFHx I),with binding preference to ERαand ERβ,respectively,were selected to evaluate their effects on proliferation and differentiation of the mouse embryonic stem cells(m ESCs).The results revealed that,similar to E_(2),50μmol/L PFHx DI accelerated the cell proliferation of the m ESCs.The PFI stimulation at the exposure concentrations of 2–50μmol/L promoted the differentiation of the m ESCs as characterized by the upregulation of differentiation-related biomarkers(i.e.,Otx2 and Dnmt3β)and downregulation of pluripotency genes(i.e.,Oct4,Nanog,Sox2,Prdm14 and Rex1).Comparatively,PFHx DI exhibited higher induction effect on the differentiation of the m ESCs than did PFHx I.The tests on ER signaling indicated that both PFI compounds induced exposure concentration-dependent expressions of ER signaling-related biomarkers(i.e.,ERα,ERβand Caveolin-1)in the m ESCs,and the downstream ER responsive genes(i.e.,c-fos,c-myc and c-jun)well responded to PFHx I stimulation.The role of ER in PFI-induced effects on the m ESCs was further validated by the antagonistic experiments using an ER inhibitor(ICI).The findings demonstrated that PFIs triggered ER signaling,and perturbed the differentiation program of the m ESCs,causing the potential health risk during early stage of development.

Abnormal energy metabolism and tau phosphorylation in the brains of middle-aged mice in response to atmospheric PM2.5 exposure

In light of the accelerated aging of the global population and the deterioration of the atmosphere pollution, we sought to clarify the potential mechanisms by which fine particulate matter（PM_（2.5）） can cause cognitive impairment and neurodegeneration through the alteration of mitochondrial structure and function. The results indicate that PM_（2.5） inhalation reduces ATP production by disrupting the aerobic tricarboxylic acid cycle and oxidative phosphorylation, thereby causing the hypophosphorylation of tau in the cortices of middle-aged mice. Furthermore, excessive reactive oxygen species generation was involved in the impairment. Interestingly, these alterations were partially reversed after exposure to PM_（2.5） ended. These findings clarify the mechanism involved in mitochondrial abnormality-related neuropathological dysfunction in response to atmospheric PM_（2.5） inhalation and provide an optimistic sight for alleviating the adverse health outcomes in polluted areas.

Effects of nitrogen dioxide and its acid mist on reactive oxygen species production and antioxidant enzyme activity in Arabidopsis plants

Nitrogen dioxide（NO2） is one of the most common and harmful air pollutants. To analyze the response of plants to NO2 stress, we investigated the morphological change, reactive oxygen species（ROS） production and antioxidant enzyme activity in Arabidopsis thaliana（Col-0） exposed to 1.7, 4, 8.5, and 18.8 mg/m3NO2. The results indicate that NO2 exposure affected plant growth and chlorophyll（Chl） content, and increased oxygen free radical（O2-）production rate in Arabidopsis shoots. Furthermore, NO2 elevated the levels of lipid peroxidation and protein oxidation, accompanied by the induction of antioxidant enzyme activities and change of ascorbate（As A） and glutathione（GSH） contents. Following this, we mimicked nitric acid mist under experimental conditions, and confirmed the antioxidant mechanism of the plant to the stress. Our results imply that NO2 and its acid mist caused pollution risk to plant systems. During the process, increased ROS acted as a signal to induce a defense response, and antioxidant status played an important role in plant protection against NO2/nitric acid mist-caused oxidative damage.

Synergistic effects of particulate matter(PM_10) and SO_2 on human non-small cell lung cancer A549 via ROS-mediated NF-κB activation

Since a real atmospheric scenario usually represents a system involving multiple pollutants, air pollution studies typically focused on describing adverse effects associated with exposure to individual pollutants cannot reflect actual health risk. Particulate matter（PM10） and sulfur dioxide（SO2） are two major pollutants derived from coal combustion processes and co-existing in coal-smoke air pollution, but their potentially synergistic toxicity remains elusive thus far. In this study, we investigated the cytotoxic responses of PM10 and SO2, singly and in binary mixtures, using human non-small cell lung cancer A549 cells, followed by clarifying the possible mechanisms for their interaction. The results indicated that the concomitant treatment of PM10 and SO2 at low concentrations led to synergistic injury in terms of cell survival and apoptosis occurrence, while PM10 and SO2 alone at the same concentrations did not cause damage to the cells. Also, radical oxygen species（ROS） production followed by nuclear factor kappa B（NF-κB） activation was involved in the above synergistic cytotoxicity, which was confirmed by the repression of the actions by an ROS inhibitor（NAC）. This implies that assessment of health risk should consider the interactions between ambient PM and gaseous copollutants.

Growing Knowledge of Stem Cells as a Novel Experimental Model in Developmental Toxicological Studies

The increasing production and extensive application of chemicals have led to their unintended release and contamination in the environment,posing a hazardous threat to wildlife and human health.Numerous studies have demonstrated that developmental toxicity could be induced by various emerging chemicals,causing abnormal embryonic and placental development,adverse pregnancy outcomes,obesity,and dysfunction of lipid metabolism in neonates.Given the currently-available experimental technology for developmental toxicological studies,an in vitro model based on stem cells showed promising performance in high-throughput screening of the early-stage developmental toxicity of emerging chemicals.In this review,the deleterious effects of environmental pollutants on stem cells were systemically assorted from the aspects of cytological dysfunction,self-renewal impairment,perturbation in embryoid body(EB)formation,and disruption of committed lineage differentiation.The toxicological data on the molecular level,including the altered expressions of gene and protein biomarkers,epigenomic regulation,and enhanced oxidative stress,were collected and summarized to provide the mechanism explanation for the link between environmental pollutant exposure and unfavorable phenotypes in stem cells.The advantage of the stem cell model in developmental toxicological studies was specifically emphasized.And the perspectives for stem cells were ultimately highlighted in the research field of environmental toxicology,especially developmental toxicology during the early stage of life.

Particulate matter(PM(2.5)) exposure season-dependently induces neuronal apoptosis and synaptic injuries

Epidemiological studies have shown that particulate matter 2.5（PM（2.5）） not only increases the incidence of cardiopulmonary illnesses but also relates to the development of neurodegenerative diseases. Considering that PM（2.5）is highly heterogeneous with regional disparity and seasonal variation, we investigated whether PM（2.5）exposure induced neuronal apoptosis and synaptic injuries in a season-dependent manner. The results indicated that PM（2.5）altered the expression of apoptosis-related proteins（mainly bax and bcl-2）, activated caspase-3 and caused neuronal apoptosis. Additionally, PM（2.5）decreased the levels of synaptic structural protein postsynaptic density（PSD-95） and synaptic functional protein N-methyl-D-aspartate（NMDA） receptor subunit（NR2B） expression. These effects occurred in a season-dependent manner, and PM（2.5）collected from the winter showed the strongest changes. Furthermore, the effect was coupled with the inhibition of phosphorylated extracellular signal-regulated kinase 1/2（p-ERK1/2） and phosphorylated c AMP-response element binding protein（p-CREB）. Based on the findings, we analyzed the correlations between the chemical composition of PM（2.5）samples and the biological effects, and confirmed that winter PM（2.5）played a major role in causing neuronal apoptosis and synaptic injuries among different season samples.

PM2.5 exposure induces age-dependent hepatic lipid metabolism disorder in female mice

Particulate matter exposure has been described to elevate the risk of lung and cardiovascular diseases.An increasing number of recent studies have indicated positive correlations between PM2.5(the fraction of airborne particles with an aerodynamic diameter less than2.5 μm) exposure and the risk of liver diseases.However,research on the effects of PM2.5exposure on liver fat synthesis,secretion,and clearance mechanisms under normal diet conditions is limited,and whether these effects are age-dependent is largely unknown.Female C57BL/6 mice at different ages(4 weeks(4 w),4 months(4 m),and 10 months(10 m))were treated with 3 mg/kg body weight of PM2.5 every other day for 4 weeks.Subsequently,the ultrastructural changes of liver,the expression of genes involved in oxidative damage and lipid metabolism in the liver were examined.Observation of hepatic ultrastructure showed more and larger lipid droplets in the livers of 4-week-old and 10-month-old mice exposed to PM2.5.Further analysis showed that PM2.5 exposure increased the expression of genes related to lipid synthesis,but decreased the expression of genes involved in lipid transport and catabolism in the livers of 10-month-old mice.Our findings suggest that exposure to PM2.5 disrupts the normal metabolism of liver lipids and induces lipid accumulation in the liver of female mice in an age-dependent manner,with older mice being more susceptible to PM2.5.