Food emulsifiers increase toxicity of food contaminants in three human GI tract cell lines.

Food products simultaneously containing both food contaminants and emulsifiers are common in baked products, coffee and chocolate. Little is known regarding how food contaminants and emulsifiers interact and alter toxicity. Recent studies have shown that while emulsifiers themselves have little toxicity, they could cause changes in the gut microenvironment and lead to issues such as increased uptake of allergens. This study examined toxic effect of two common process contaminants acrylamide (AA) and benzo [a]pyrene (BAP) combined with food emulsifiers polyoxyethylene sorbitan monooleate (TW) or glycerol monostearate (G). In liver cell line HepG2 and gastrointestinal cell lines HIEC6 and Caco-2, toxicities of AA and BAP were increased by TW but not by G as indicated by decrease in IC50 values. Addition of TW also exacerbated gene expression changes caused by AA or BAP. Cellular uptake and cell membrane permeability were enhanced by TW but not by G, but tight junction proteins of Caco-2 monolayer was impacted by both emulsifiers. These results suggested that TW could increase toxicity of AA and BAP through increasing cell permeability thus chemical uptake and potentially through other interactions. The study is to draw the attention of regulators on the potential synergistic interaction of co-occurring chemicals in food.

Hemodynamics regulate spatiotemporal artery muscularization in the developing circle of Willis.

Brain arteries are wrapped by vascular smooth muscle cells (VSMCs). Fully differentiated VSMCs are important for brain artery homeostasis, and they are lost in several cerebrovascular diseases. How healthy VSMCs differentiate on different brain arteries during development is unclear. Such knowledge will help regenerate lost VSMCs in brain arteriopathy. To answer this question, we studied the developmental muscularization of the zebrafish circle of Willis (CW) arteries, the major arterial loop that supplies blood to the brain in all vertebrates. We found that artery specification of CW endothelial cells (ECs) happens after they migrate from primitive veins to form CW arteries. VSMCs differentiate from pdgfrb+ common vascular mural cell progenitors at the time when embryo circulation starts and progress temporally and spatially from anterior to posterior CW arteries. Computational fluid dynamic simulation confirms that earlier VSMC differentiation coincide with higher pulsatile flow hemodynamics in anterior CW arteries. Pulsatile blood flow induces the differentiation of human brain pdgfrb+ progenitors into VSMCs and reducing pulsatile blood flow by blocking the zebrafish embryo heartbeat after pdgfrb+ recruitment but before VSMC differentiation limits the number of mature VSMCs. Congruently, the flow responsive transcription factor klf2a is activated in ECs before VSMC differentiation and knockdown delays VSMC differentiation on CW arteries. Overall, our data place hemodynamic activation of endothelial klf2a signaling as key determinant of spatiotemporal VSMC differentiation on CW arteries.

Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.

Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta-gonad-mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.

Selenium Nanoparticles (SeNPs) Immunomodulation Is More Than Redox Improvement: Serum Proteomics and Transcriptomic Analyses.

Selenium nanoparticles (SeNPs) are a novel elemental form selenium and often reported to possess beneficial bioactivities such as anticancer, promoting bone growth and immunomodulation. Our previous study demonstrated that chitosan-stabilized SeNPs have strong activity in immunomodulation. However, the mechanism underlying the immunomodulation of SeNPs is still unknown. The aim of this study is to identify the molecular mechanisms involved in SeNP-induced immunomodulation. Using zebrafish, as a common immunological animal model with a highly conserved molecular mechanism with other vertebrates, we conducted serum proteomic and tissue transcriptome analyses on individuals fed with SeNP in healthy or disease conditions. We also compared differences between SeNPs and an exogenous antioxidant Trolox in immune activity and redox regulation. Our results suggest that the immunomodulation activity was highly related to antioxidant activity and lipid metabolism. Interestingly, the biological functions enhanced by SeNP were almost identical in the healthy and disease conditions. However, while the SeNP was suppressing ROS in healthy individuals, it promoted ROS formation during disease condition. This might be related to the defense mechanism against pathogens. SOD and NFkß appeared to be the key molecular switch changing effect of SeNPs when individuals undergo infection, indicating the close relationship between immune and redox regulation.

Dietary chitosan-selenium nanoparticle (CTS-SeNP) enhance immunity and disease resistance in zebrafish.

Selenium (Se) is an essential micronutrient for human and animals. It plays an important role in antioxidative stress, selenoenzymes regulation and immunomodulation. In this study, two common immunostimulants chitosan (CTS) and Se were used to synthesize nanoparticles (CTS-SeNP). Immunomodulation of CTS-SeNP were explored in wild-type zebrafish (Danio rerio). Dietary supplementation of CTS-SeNP enhanced lysozyme activity, phagocytic respiratory burst as well as splenocytes proliferation stimulated by LPS and ConA. CTS-SeNP showed immunomodulation effect from 5 to 20 µg/g but the best outcome was observed at 10 µg/g. Immunomodulation effect were rapidly induced after 3-9d and can sustain to 60. The zebrafish fed with 10 µg/g CTS-SeNP also showed 26.7% higher survival rate than the control after intraperitoneal injection of common bacterium Aeromonas hydrophila. Our results suggested that CTS-SeNP is an effective immunostimulant to fish and has potential application in aquaculture.

Maternal dietary exposure to selenium nanoparticle led to malformation in offspring.

Selenium (Se) is an essential element and its biological activity is related to its speciation. It is also well-known that in excess it can cause teratogenesis in fish and birds. In this study we compared dietary toxicity of elemental selenium nanoparticles (SeNPs) with selenite and selenomethionine (Se-Met). Japanese medaka (Oryzias latipes) was used as a laboratory model to determine Se effects on adults and their offspring. Adult females were individually exposed using a dry diet fortified with 0, 10 or 20 µg/g of the three Se species for 7 days and then allowed to breed for 3 days. Fertilization rate and the proportion of malformed offspring were examined. The three Se diets led to significant increase in maternal tissue Se concentration in the order of Se-Met >>selenite > SeNP. However, in terms of proportion of malformed offspring, the effect of Se-Met = selenite > SeNP. The malformations included pericardial edema and craniofacial changes, which were typical for Se toxicity. The mismatch of maternal ovary Se concentration and proportion of malformed offspring suggested total Se concentration is a poor predictor of toxicity and teratogenesis. Comparing expression of four genes related to oxidative stress in maternal tissue also showed that there were significant differences in expression patterns between three Se diets in the order of selenite = SeNP > Se-Met. Our results showed that SeNPs cause similar toxicity as other Se species but require further study to elucidate the underlying mechanism.