MYC acetylated lysine residues drive oncogenic cell transformation and regulate select genetic programs for cell adhesion-independent growth and survival.

The MYC oncogenic transcription factor is acetylated by the p300 and GCN5 histone acetyltransferases. The significance of MYC acetylation and the functions of specific acetylated lysine (AcK) residues have remained unclear. Here, we show that the major p300-acetylated K148(149) and K157(158) sites in human (or mouse) MYC and the main GCN5-acetylated K323 residue are reversibly acetylated in various malignant and nonmalignant cells. Oncogenic overexpression of MYC enhances its acetylation and alters the regulation of site-specific acetylation by proteasome and deacetylase inhibitors. Acetylation of MYC at different K residues differentially affects its stability in a cell type-dependent manner. Lysine-to-arginine substitutions indicate that although none of the AcK residues is required for MYC stimulation of adherent cell proliferation, individual AcK sites have gene-specific functions controlling select MYC-regulated processes in cell adhesion, contact inhibition, apoptosis, and/or metabolism and are required for the malignant cell transformation activity of MYC. Each AcK site is required for anchorage-independent growth of MYC-overexpressing cells in vitro, and both the AcK148(149) and AcK157(158) residues are also important for the tumorigenic activity of MYC transformed cells in vivo. The MYC AcK site-specific signaling pathways identified may offer new avenues for selective therapeutic targeting of MYC oncogenic activities.

Assessment and Comparison of Early Developmental Toxicity of Six Per- and Polyfluoroalkyl Substances with Human Embryonic Stem Cell Models.

Per- and polyfluoroalkyl substances (PFAS) are extensively utilized in varieties of products and tend to accumulate in the human body including umbilical cord blood and embryos/fetuses. In this study, we conducted an assessment and comparison of the potential early developmental toxicity of perfluorooctanoic acid (PFOA), undecafluorohexanoic acid (PFHxA), heptafluorobutyric acid, perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate, and perfluorobutyric acid at noncytotoxic concentrations relevant to human exposure using models based on human embryonic stem cells in both three-dimensional embryoid body (EB) and monolayer differentiation configurations. All six compounds influenced the determination of cell fate by disrupting the expression of associated markers in both models and, in some instances, even led to alterations in the formation of cystic EBs. The expression of cilia-related gene IFT122 was significantly inhibited. Additionally, PFOS and PFOA inhibited ciliogenesis, while PFOA specifically reduced the cilia length. Transcriptome analysis revealed that PFOS altered 1054 genes and disrupted crucial signaling pathways such as WNT and TGF-ß, which play integral roles in cilia transduction and are critical for early embryonic development. These results provide precise and comprehensive insights into the potential adverse health effects of these six PFAS compounds directly concerning early human embryonic development.

Transcriptomic Integration Analyses Uncover Common Bisphenol A Effects Across Species and Tissues Primarily Mediated by Disruption of JUN/FOS, EGFR, ER, PPARG, and P53 Pathways.

Bisphenol A (BPA) is a common endocrine disruptor widely used in the production of electronic, sports, and medical equipment, as well as consumer products like milk bottles, dental sealants, and thermal paper. Despite its widespread use, current assessments of BPA exposure risks remain limited due to the lack of comprehensive cross-species comparative analyses. To address this gap, we conducted a study aimed at identifying genes and fundamental molecular processes consistently affected by BPA in various species and tissues, employing an effective data integration method and bioinformatic analyses. Our findings revealed that exposure to BPA led to significant changes in processes like lipid metabolism, proliferation, and apoptosis in the tissues/cells of mammals, fish, and nematodes. These processes were found to be commonly affected in adipose, liver, mammary, uterus, testes, and ovary tissues. Additionally, through an in-depth analysis of signaling pathways influenced by BPA in different species and tissues, we observed that the JUN/FOS, EGFR, ER, PPARG, and P53 pathways, along with their downstream key transcription factors and kinases, were all impacted by BPA. Our study provides compelling evidence that BPA indeed induces similar toxic effects across different species and tissues. Furthermore, our investigation sheds light on the underlying molecular mechanisms responsible for these toxic effects. By uncovering these mechanisms, we gain valuable insights into the potential health implications associated with BPA exposure, highlighting the importance of comprehensive assessments and awareness of this widespread endocrine disruptor.

Pollution effects on retinal health: A review on current methodologies and findings.

In our daily life, we are exposed to numerous industrial chemicals that may be harmful to the retina, which is a delicate and sensitive part of our eyes. This could lead to irreversible changes and cause retinal diseases or blindness. Current retinal environmental health studies primarily utilize animal models, isolated mammalian retinas, animal- or human-derived retinal cells, and retinal organoids, to address both pre- and postnatal exposure. However, as there is limited toxicological information available for specific populations, human induced pluripotent stem cell (hiPSC)-induced models could be effective tools to supplement such data. In order to obtain more comprehensive and reliable toxicological information, we need more appropriate models, novel evaluation methods, and computational technologies to develop portable equipment. This review mainly focused on current toxicology models with particular emphasis on retinal organoids, and it looks forward to future models, analytical methods, and equipment that can efficiently and accurately evaluate retinal toxicity.

Development of a simplified human embryonic stem cell-based retinal pre-organoid model for toxicity evaluations of common pollutants.

OBJECTIVE: To explore the retinal toxicity of pharmaceuticals and personal care products (PPCPs), flame retardants, bisphenols, phthalates, and polycyclic aromatic hydrocarbons (PAHs) on human retinal progenitor cells (RPCs) and retinal pigment epithelial (RPE) cells, which are the primary cell types at the early stages of retinal development, vital for subsequent functional cell type differentiation, and closely related to retinal diseases. MATERIALS AND METHODS: After 23 days of differentiation, human embryonic stem cell (hESC)-based retinal pre-organoids, containing RPCs and RPE cells, were exposed to 10, 100, and 1000 nM pesticides (butachlor, terbutryn, imidacloprid, deltamethrin, pendimethalin, and carbaryl), flame retardants (PFOS, TBBPA, DBDPE, and TDCIPP), PPCPs (climbazole and BHT), and other typical pollutants (phenanthrene, DCHP, and BPA) for seven days. Then, mRNA expression changes were monitored and compared. RESULTS: (1) The selected pollutants did not show strong effects at environmental and human-relevant concentrations, although the effects of flame retardants were more potent than those of other categories of chemicals. Surprisingly, some pollutants with distinct structures showed similar adverse effects. (2) Exposure to pollutants induced different degrees of cell detachment, probably due to alterations in extracellular matrix and/or cell adhesion. CONCLUSIONS: In this study, we established a retinal pre-organoid model suitable for evaluating multiple pollutants' effects, and pointed out the potential retinal toxicity of flame retardants, among other pollutants. Nevertheless, the potential mechanisms of toxicity and the effects on cell detachment are still unclear and deserve further exploration. Additionally, this model holds promise for screening interventions aimed at mitigating the detrimental effects of these pollutants.

Tox21-Based Comparative Analyses for the Identification of Potential Toxic Effects of Environmental Pollutants.

Chemical pollution has become a prominent environmental problem. In recent years, quantitative high-throughput screening (qHTS) assays have been developed for the fast assessment of chemicals' toxic effects. Toxicology in the 21st Century (Tox21) is a well-known and continuously developing qHTS project. Recent reports utilizing Tox21 data have mainly focused on setting up mathematical models for in vivo toxicity predictions, with less attention to intuitive qHTS data visualization. In this study, we attempted to reveal and summarize the toxic effects of environmental pollutants by analyzing and visualizing Tox21 qHTS data. Via PubMed text mining, toxicity/structure clustering, and manual classification, we detected a total of 158 chemicals of environmental concern (COECs) from the Tox21 library that we classified into 13 COEC groups based on structure and activity similarities. By visualizing these COEC groups' bioactivities, we demonstrated that COECs frequently displayed androgen and progesterone antagonistic effects, xenobiotic receptor agonistic roles, and mitochondrial toxicity. We also revealed many other potential targets of the 13 COEC groups, which were not well illustrated yet, and that current Tox21 assays may not correctly classify known teratogens. In conclusion, we provide a feasible method to intuitively understand qHTS data.

Perfluorinated Iodine Alkanes Promoted Neural Differentiation of mESCs by Targeting miRNA-34a-5p in Notch-Hes Signaling.

The neurodevelopmental process is highly vulnerable to environmental stress from exposure to endocrine-disrupting chemicals. Perfluorinated iodine alkanes (PFIs) possess estrogenic activities, while their potential neurodevelopmental toxicity remains blurry. In the present study, the effects of two PFIs, including dodecafluoro-1,6-diiodohexane (PFHxDI) and tridecafluorohexyl iodide (PFHxI), were investigated in the neural differentiation of the mouse embryonic stem cells (mESCs). Without influencing the cytobiological process of the mESCs, PFIs interfered the triploblastic development by increasing ectodermal differentiation, thus promoting subsequent neurogenesis. The temporal regulation of PFIs in Notch-Hes signaling through the targeting of mmu-miRNA-34a-5p provided a substantial explanation for the underlying mechanism of PFI-promoted mESC commitment to the neural lineage. The findings herein provided new knowledge on the potential neurodevelopmental toxicities of PFIs, which would help advance the health risk assessment of these kinds of emerging chemicals.

A genome-wide RNAi screen identifies opposing functions of Snai1 and Snai2 on the Nanog dependency in reprogramming.

Nanog facilitates embryonic stem cell self-renewal and induced pluripotent stem cell generation during the final stage of reprogramming. From a genome-wide small interfering RNA screen using a Nanog-GFP reporter line, we discovered opposing effects of Snai1 and Snai2 depletion on Nanog promoter activity. We further discovered mutually repressive expression profiles and opposing functions of Snai1 and Snai2 during Nanog-driven reprogramming. We found that Snai1, but not Snai2, is both a transcriptional target and protein partner of Nanog in reprogramming. Ectopic expression of Snai1 or depletion of Snai2 greatly facilitates Nanog-driven reprogramming. Snai1 (but not Snai2) and Nanog cobind to and transcriptionally activate pluripotency-associated genes including Lin28 and miR-290-295. Ectopic expression of miR-290-295 cluster genes partially rescues reprogramming inefficiency caused by Snai1 depletion. Our study thus uncovers the interplay between Nanog and mesenchymal factors Snai1 and Snai2 in the transcriptional regulation of pluripotency-associated genes and miRNAs during the Nanog-driven reprogramming process.

Graphene Quantum Dots Disrupt Embryonic Stem Cell Differentiation by Interfering with the Methylation Level of Sox2.

The tremendous potential for graphene quantum dots (GQDs) in biomedical applications has led to growing concerns of their health risks in human beings. However, present studies mainly focused on oxidative stress, apoptosis, and other general toxicity effects; the knowledge on the developmental toxicity and the related regulatory mechanisms is still far from sufficient. Our study revealed the development retardation of mouse embryonic stem cells (mESCs) caused by GQDs with a novel DNA methylation epigenetic mechanism. Specifically, GQDs were internalized into cells mainly via energy-dependent endocytosis, and a significant fraction of internalized GQDs remained in the cells even after a 48-h clearance period. Albeit with unobservable cytotoxicity or any influences on cell pluripotency, significant retardation was found in the in vitro differentiation of the mESCs into embryoid bodies (EBs) with the upregulation of Sox2 levels in GQD pretreatment groups. Importantly, this effect could be contributed by GQD-induced inhibition in CpG methylation of Sox2 through altering methyltransferase and demethyltransferase transcriptional expressions, and the demethyltransferase inhibitor, bobcat339 hydrochloride, reduced GQD-induced upregulation of Sox2. The current study first demonstrated that GQDs compromised the differentiation program of the mESCs, potentially causing development retardation. Exposure to this nanomaterial during gestation or early developmental period would cause adverse health risks and is worthy of more attention.

Development of Human Lung Induction Models for Air Pollutants' Toxicity Assessment.

There is an urgent need for reliable and effective models to study air pollution health effects on human lungs. Here, we report the utilization of human pluripotent stem cell (hPSC) induction models for human lung progenitor cells (hLPs) and alveolar type 2 epithelial cell-like cells (ATLs) for the toxicity assessment of benzo(a)pyrene, nano-carbon black, and nano-SiO2, as common air pollutants. We induced hPSCs to generate ATLs, which recapitulated key features of human lung type 2 alveolar epithelial cells, and tested the induction models for cellular uptake of nanoparticles and toxicity evaluations. Our findings reveal internalization of nano-carbon black, dose-dependent uptake of nano-SiO2, and interference with surfactant secretion in ATLs exposed to benzo(a)pyrene/nano-SiO2. Thus, hLP and ATL induction models could facilitate the evaluation of environmental pollutants potentially affecting the lungs. In conclusion, this is one of the first studies that managed to adopt hPSC pulmonary induction models in toxicology studies.

Tetrabromobisphenol A (TBBPA): A controversial environmental pollutant.

Tetrabromobisphenol A (TBBPA) is one of the most widely used brominated flame retardants and is extensively used in electronic equipment, furniture, plastics, and textiles. It is frequently detected in water, soil, air, and organisms, including humans, and has raised concerns in the scientific community regarding its potential adverse health effects. Human exposure to TBBPA is mainly via diet, respiration, and skin contact. Various in vivo and in vitro studies based on animal and cell models have demonstrated that TBBPA can induce multifaceted effects in cells and animals, and potentially exert hepatic, renal, neural, cardiac, and reproductive toxicities. Nevertheless, other reports have claimed that TBBPA might be a safe chemical. In this review, we re-evaluated most of the published TBBPA toxicological assessments with the goal of reaching a conclusion about its potential toxicity. We concluded that, although low TBBPA exposure levels and rapid metabolism in humans may signify that TBBPA is a safe chemical for the general population, particular attention should be paid to the potential effects of TBBPA on early developmental stages.

The short-chain perfluorinated compounds PFBS, PFHxS, PFBA and PFHxA, disrupt human mesenchymal stem cell self-renewal and adipogenic differentiation.

Per- and polyfluorinated alkyl substances (PFASs) are commonly used in industrial processes and daily life products. Because they are persistent, they accumulate in the environment, wildlife and humans. Although many studies have focused on two of the most representative PFASs, PFOS and PFOA, the potential toxicity of short-chain PFASs has not yet been given sufficient attention. We used a battery of assays to evaluate the toxicity of several four-carbon and six-carbon perfluorinated sulfonates and carboxyl acids (PFBS, PFHxS, PFBA and PFHxA), with a human mesenchymal stem cell (hMSC) system. Our results demonstrate significant cyto- and potential developmental toxicity for all the compounds analyzed, with shared but also distinct mechanisms of toxicity. Moreover, the effects of PFBS and PFHxS were stronger than those of PFBA and PFHxA, but occurred at higher doses compared to PFOS or PFOA.

A human embryonic stem cell-based in vitro model revealed that ultrafine carbon particles may cause skin inflammation and psoriasis.

Air pollution has been linked to many health issues, including skin conditions, especially in children. Among all the atmospheric pollutants, ultrafine particles have been deemed very dangerous since they can readily penetrate the lungs and skin, and be absorbed into the bloodstream. Here, we employed a human embryonic stem cell (hESC)-based differentiation system towards keratinocytes, to test the effects of ultrafine carbon particles, which mimic ambient ultrafine particles, at environment related concentrations. We found that 10 ng/mL to 10 µg/mL ultrafine carbon particles down-regulated the expression of the pluripotency marker SOX2 in hESCs. Moreover, 1 µg/mL to 10 µg/mL carbon particle treatments disrupted the keratinocyte differentiation, and up-regulated inflammation- and psoriasis-related genes, such as IL-1ß, IL-6, CXCL1, CXCL2, CXCL3, CCL20, CXCL8, and S100A7 and S100A9, respectively. Overall, our results provide a new insight into the potential developmental toxicity of atmospheric ultrafine particles.

Toxicogenomic analyses of the effects of BDE-47/209, TBBPA/S and TCBPA on early neural development with a human embryonic stem cell in vitro differentiation system.

Flame retardants are detected in the environment worldwide, and thus pose great risks to human health. The potential effects of these chemicals on the development of the central nervous system, have recently raised public concern. In this study, to explore the toxicity of these chemicals during the early developmental stages of the human central nervous system, we induced human embryonic stem cells to differentiate into neural ectoderm in the presence of five halogenated flame retardants, BDE-47, BDE-209, TBBPA, TBBPS and TCBPA, individually or in combination. We identified a set of neural development-related biological processes that responded to these chemicals, by analyzing the whole transcriptional changes. We confirmed the RNA-seq results by qRT-PCR and found that transcription factors crucial for neural development, such as ZIC1, ZIC3, HES3, IGFBP3 and DLX5, were dysregulated by those chemicals. In addition, the five flame retardants might also influence axon growth/guidance and neuron transmission-related processes, by dysregulating genes including CNTN2, SLIT1, LRRC4C, RELN, CBLN1, CHRNB4 and GDF7. Furthermore, the chemical treatments seemed to interfere with the WNT and AHR signaling pathways. Overall, our findings revealed that BDE-209 had similar toxicity as BDE-47, whereas TBBPS and TCBPA might not be safe alternatives to TBBPA. Interestingly, we observed no obvious synergistic effects when we mixed those five flame retardants together.

NANOG-dependent function of TET1 and TET2 in establishment of pluripotency.

Molecular control of the pluripotent state is thought to reside in a core circuitry of master transcription factors including the homeodomain-containing protein NANOG, which has an essential role in establishing ground state pluripotency during somatic cell reprogramming. Whereas the genomic occupancy of NANOG has been extensively investigated, comparatively little is known about NANOG-associated proteins and their contribution to the NANOG-mediated reprogramming process. Using enhanced purification techniques and a stringent computational algorithm, we identify 27 high-confidence protein interaction partners of NANOG in mouse embryonic stem cells. These consist of 19 previously unknown partners of NANOG that have not been reported before, including the ten-eleven translocation (TET) family methylcytosine hydroxylase TET1. We confirm physical association of NANOG with TET1, and demonstrate that TET1, in synergy with NANOG, enhances the efficiency of reprogramming. We also find physical association and reprogramming synergy of TET2 with NANOG, and demonstrate that knockdown of TET2 abolishes the reprogramming synergy of NANOG with a catalytically deficient mutant of TET1. These results indicate that the physical interaction between NANOG and TET1/TET2 proteins facilitates reprogramming in a manner that is dependent on the catalytic activity of TET1/TET2. TET1 and NANOG co-occupy genomic loci of genes associated with both maintenance of pluripotency and lineage commitment in embryonic stem cells, and TET1 binding is reduced upon NANOG depletion. Co-expression of NANOG and TET1 increases 5-hydroxymethylcytosine levels at the top-ranked common target loci Esrrb and Oct4 (also called Pou5f1), resulting in priming of their expression before reprogramming to naive pluripotency. We propose that TET1 is recruited by NANOG to enhance the expression of a subset of key reprogramming target genes. These results provide an insight into the reprogramming mechanism of NANOG and uncover a new role for 5-methylcytosine hydroxylases in the establishment of naive pluripotency.

New insights into mechanism of bisphenol analogue neurotoxicity: implications of inhibition of O-GlcNAcase activity in PC12 cells.

Bisphenol analogues including bisphenol A and its derivatives are ubiquitous environmental contaminants and have been linked to adverse neurodevelopment effects on animals and humans. Most toxicological research focused on estrogen receptor mediated pathways and did not comprehensively clarify the observed toxicity. O-GlcNAcase (OGA), the highest level in brain, plays a critical role in controlling neuronal functions at multi-levels from molecule to animal behaviors. In this work, we intend to investigate the underlying molecular mechanisms for the neurotoxicity of bisphenol analogues by identifying their cellular targets and the resultant effects. The inhibitory actions of seven bisphenol analogues on the OGA activity at molecular level were investigated by our developed electrochemical biosensor. We found that their potency varied with substituent groups, in which tetrabromo bisphenol A (TBBPA) was the strongest. The seven bisphenol analogues (0-100 µM exposure) significantly inhibited OGA activity and up-regulated protein O-GlcNAcylation level in PC12 cells. Inhibition of OGA by bisphenol analogues further induced intracellular calcium, ROS, inflammation, repressed proliferation, interfered with cell cycle, induced apoptosis. And especially, 10 µM tetrabromo bisphenol A (TBBPA) exposure could impair the growth and development of neurite in human neural stem cells (hNSCs). Molecular docking for OGA/bisphenol analogue complexes revealed the hydrophobicity-dominated inhibition potency. OGA, as a new cellular target of bisphenol analogues, would illuminate the molecular mechanism of bisphenol analogues neurotoxicity.

Genetic diversity of diazotrophs and total bacteria in the phyllosphere of Pyrus serotina, Prunus armeniaca, Prunus avium, and Vitis vinifera.

The phyllosphere, which supports a large number of microorganisms, represents the interface between the aboveground parts of plants and air. In this study, four nifH clone libraries were constructed from the phyllosphere of Pyrus serotina (L), Vitis vinifera (P), Prunus armeniaca (X), and Prunus avium (Y). Clones related to Skermanella (L, 12.1%; X, 15.6%; Y, 62.5%; P 70.8%), Bradyrhizobium (X, 2.1%; P, 15.1%; L, 63.7%), Erwinia (X, 68.8%), Pseudomonas (L, 3.3%; P, 7.6%), and Chroococcidiopsis (P, 0.9%; L, 4.4%, X; 5.2%, Y; 19.6%) were present at high percentages, highlighting their critical role in contributing nitrogen to the phyllosphere ecosystem. The 16S rDNA sequence analysis suggested that phyllosphere-associated bacteria were affiliated with a wide range of taxa, encompassing members from Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Deltaproteobacteria, Actinobacteria, Bacteroidetes, Firmicutes, Cyanobacteria, Tenericutes, and Deinococcus-Thermus. Additionally, the abundance of the nifH gene and 16S rDNA was assessed with quantitative PCR. The number of copies of nifH and 16S rDNA ranged from 1.14 × 103 to 1.49 × 104 and from 3.72 × 106 to 7.02 × 107 copies/g fresh leaf sample, respectively. In conclusion, our work sheds light on the microbial communities of the phyllosphere that are important for plant growth. Moreover, we observed a unique composition of nitrogen-fixing bacteria in each phyllosphere sample, suggesting the existence of specific interactions between these functional microorganism and plants, which may provide information or be a reference for the development of bacterial fertilizers.

Typical halogenated flame retardants affect human neural stem cell gene expression during proliferation and differentiation via glycogen synthase kinase 3 beta and T3 signaling.

2',2',4,4'-tetrabromo diphenyl ether (BDE-47), one of the most abundant congeners of commercial pentaBDE utilized as flame retardants, has been phased out of production due to its potential neural toxicity and endocrine disrupting activities, and yet still present in the environment. Several alternatives to BDE-47, including tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), tetrachlorobisphenol A (TCBPA) and decabromodiphenyl ether (BDE-209), are presently employed without restrictions and their potential toxic effects on human neural development are still unclear. In this study, we utilized a human neural stem cell (hNSC)-based system to evaluate the potential developmental neurotoxic effects of the above-mentioned five chemicals, at environment and human exposure relevant concentrations. We found that those compounds slightly altered the expression of hNSC identity markers (SOX2, SOX3 and NES), without impairing cell viability or proliferation, in part by either modulating glycogen synthase kinase 3 beta (GSK3ß) signaling (TBBPS, TCBPA and BDE-47), and slightly disturbing the NOTCH pathway (TBBPA, TBBPS and TCBPA). Moreover, the five chemicals seemed to alter hNSC differentiation by perturbing triiodothyronine (T3) cellular signaling. Thus, our findings suggest that the five compounds, especially TBBPS, TCBPA, and BDE-47, may affect hNSC self-renewal and differentiation abilities and potentially elicit neural developmental toxicity.

Establishment of a human embryonic stem cell-based liver differentiation model for hepatotoxicity evaluations.

The liver is one of the major targets of hormones, including thyroid hormones (THs), and many industrial chemicals, such as endocrine-disrupting chemicals. Those compounds may permeate the placenta barrier and pose a risk for embryonic development. Therefore, it is necessary to assess the toxic effects of those kind of industrial chemicals during liver development. In this study, to mimic liver specification in vitro, we differentiated human embryonic stem cells (ESCs) into functional hepatocyte-like cells. We performed this differentiation process in presence of two THs, triiodothyronine (T3) and thyroxine (T4), with the purpose of identifying biomarkers for toxicity screening. TH exposure (3, 30 and 300 nM) yielded to hepatocytes with impaired glycogen storage ability and abnormal lipid droplets' accumulation. Global gene expression analysis by RNA-seq identified a number of genes responsible for hepatic differentiation and function which were affected by 30 nM T3 and T4. Those differentially expressed genes were used to assess the potential developmental liver toxicity of two famous environmental pollutants, 2, 2, 4, 4-tetrabromodiphenyl ether (BDE-47) and decabromodiphenyl ether (BDE-209), at 10 nM to 1 µM treatments. Our findings demonstrate that BDE-47 and BDE-209, dysregulated pathways such as "chemical carcinogenesis", "steroid hormone biosynthesis" and "drug metabolism-cytochrome P450". Moreover, we were able to identify a set of 17 biomarkers, very useful to predict the potential developmental hepatotoxicity of industrial chemicals.

Environmental and human relevant PFOS and PFOA doses alter human mesenchymal stem cell self-renewal, adipogenesis and osteogenesis.

PFOS and PFOA are two of the most abundant perfluorinated compounds (PFCs) in the environment. Previous studies have reported they have a long half-life (up to five years) once they enter into the human body. Moreover, they can potentially promote the adipogenic process by activating PPARγ. However, little is known about PFOS and PFOA chronic health impacts on humans. In this study, we employed primary human mesenchymal stem cells (hMSCs) and demonstrated that PFOS and PFOA exerted acute cytotoxicity and affected adipogenesis and osteogenesis at environmental and human relevant doses. In fact, PFOS and PFOA impaired the proper expression of CD90 (a surface antigen highly enriched in undifferentiated hMSCs) and promoted adipogenesis, presumably via their interaction with PPARγ. Moreover, PFOA partly disturbed osteogenesis. Thus, our findings not only validated the health risks of PFOS and PFOA, but also revealed new potential long-term PFOS/PFOA impacts on humans.