Design and structure-activity relationships of ether-linked alkylides: Hybrids of 3-O-descladinosyl macrolides and quinolone motifs.

Ketolides (3-keto) such as TE-802 and acylides (3-O-acyl) like TEA0929 are ineffective against constitutively resistant pathogens harboring erythromycin ribosomal methylation (erm) genes. Following our previous work on alkylides (3-O-alkyl), we explored the structure-activity relationships of hybrids combining (R/S) 3-descladinosyl erythromycin with 6/7-quinolone motifs, featuring extended ether-linked spacers, with a focus on their efficacy against pathogens bearing constitutive erm gene resistance. Optimized compounds 17a and 31f not only reinstated efficacy against inducibly resistant pathogens but also demonstrated significantly augmented activities against constitutively resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes, which are typically refractory to existing C-3 modified macrolides. Notably, hybrid 31f (coded ZN-51) represented a pioneering class of agents distinguished by its dual modes of action, with ribosomes as the primary target and topoisomerases as the secondary target. As a novel chemotype of macrolide-quinolone hybrids, alkylide 31f is a valuable addition to our armamentarium against macrolide-resistant bacteria.

Prediction of PFAS bioaccumulation in different plant tissues with machine learning models based on molecular fingerprints.

Due to the wastewater irrigation or biosolid application, per- and polyfluoroalkyl substances (PFASs) have been widely detected in agriculture soil and hence crops or vegetables. Consumption of contaminated crops and vegetables is considered as an important route of human exposure to PFASs. Machine learning (ML) models have been developed to predict PFAS uptake by plants with majority focus on roots. However, ML models for predicting accumulation of PFASs in above ground edible tissues have yet to be investigated. In this study, 811 data points covering 22 PFASs represented by molecular fingerprints and 5 plant categories (namely the root class, leaf class, cereals, legumes, and fruits) were used for model development. The Extreme Gradient Boosting (XGB) model demonstrated the most favorable performance to predict the bioaccumulation factors (BAFs) in all the 4 plant tissues (namely root, leaf, stem, and fruit) achieving coefficients of determination R2 as 0.82-0.93. Feature importance analysis showed that the top influential factors for BAFs varied among different plant tissues, indicating that model developed for root concentration prediction may not be feasible for above ground parts. The XGB model's performance was further demonstrated by comparing with data from pot experiments measuring BAFs of 12 PFASs in lettuce. The correlation between predicted and measured results was favorable for BAFs in both lettuce roots and leaves with R2 values of 0.76 and 0.81. This study developed a robust approach to comprehensively understand the uptake of PFASs in both plant roots and above ground parts, offering key insights into PFAS risk assessment and food safety.

Immune function of a C-type lectin with long tandem repeats and abundant threonine in the ridgetail white prawn Exopalaemon carinicauda.

C-type lectins (CTLs) are an important class of pattern recognition receptors (PRRs) that exhibit structural and functional diversity in invertebrates. Repetitive DNA sequences are ubiquitous in eukaryotic genomes, representing distinct modes of genome evolution and promoting new gene generation. Our study revealed a new CTL that is composed of two long tandem repeats, abundant threonine, and one carbohydrate recognition domain (CRD) in Exopalaemon carinicauda and has been designated EcTR-CTL. The full-length cDNA of EcTR-CTL was 1242 bp long and had an open reading frame (ORF) of 999 bp that encoded a protein of 332 amino acids. The genome structure of EcTR-CTL contains 4 exons and 3 introns. The length of each repeat unit in EcTR-CTL was 198 bp, which is different from the short tandem repeats reported previously in prawns and crayfish. EcTR-CTL was abundantly expressed in the intestine and hemocytes. After Vibrio parahaemolyticus and white spot syndrome virus (WSSV) challenge, the expression level of EcTR-CTL in the intestine was upregulated. Knockdown of EcTR-CTL downregulated the expression of anti-lipopolysaccharide factor, crustin, and lysozyme during Vibrio infection. The recombinant CRD of EcTR-CTL (rCRD) could bind to bacteria, lipopolysaccharides, and peptidoglycans. Additionally, rCRD can directly bind to WSSV. These findings indicate that 1) CTLs with tandem repeats may be ubiquitous in crustaceans, 2) EcTR-CTL may act as a PRR to participate in the innate immune defense against bacteria via nonself-recognition and antimicrobial peptide regulation, and 3) EcTR-CTL may play a positive or negative role in the process of WSSV infection by capturing virions.

Differential expression of sNPF in male and female eyestalk leading to sex dimorphism of AMP expression in Procambarus clarkii intestine.

Antimicrobial peptide (AMP) is an important component of crustaceans' innate immune system. In this study, a short neuropeptide F (sNPF) gene (Pc-sNPF) and a Forkhead box O (FOXO) gene (PcFOXO) from Procambarus clarkii were identified. Analysis findings showed that the expression level of AMP genes differed between male and female P. clarkii. Furthermore, Pc-sNPF and PcFOXO were related to the sex dimorphism of AMP. Knockdown of Pc-sNPF in the eyestalk significantly upregulated the expression of PcFOXO and two anti-lipopolysaccharide factors (PcALF4 and PcALFL) in the intestine of P. clarkii. The expression of PcFOXO in the intestine of female P. clarkii was higher than in that of males. Results from RNA interference revealed that PcFOXO positively regulated the expression of PcALF4 and PcALFL in the intestine of male and female P. clarkii. In summary, our study showed that differences in Pc-sNPF expression in eyestalk of male and female P. clarkii leading to sex dimorphism of AMP expression in the intestine are mediated by the sNPF-FOXO-AMP signal pathway called the eyestalk-intestine axis.

Regulating the absorption and excretion of perfluorooctane sulfonate and its alternatives through influencing enterohepatic circulation.

Enterohepatic circulation has been reported to play a significant role in the bioaccumulation of PFASs. In this study, the tissue distribution and excretion of PFOS and its alternatives, namely 6:2 and 8:2 fluorotelomer sulfonic acid (FTSA) was investigated using a mouse assay with a focus on role of enterohepatic circulation. Liver was the primarily accumulating organ for PFOS and 8:2 FTSA (33.4 % and 25.8 % of total doses absorbed after 14 days), whereas 65 % of 6:2 FTSA was excreted via urine within 24 h. Peak levels of 8:2 FTSA and PFOS were found in the gallbladder, implying the important role of enterohepatic circulation in PFASs reabsorption. The role of enterohepatic circulation was further evaluated through co-exposure of 8:2 FTSA and PFOS with medicines (namely metformin (MET) and ursodeoxycholic acid (UDCA)). MET reduced accumulation of 8:2 FTSA and PFOS in the liver by 68.6 % and 65.8 %, through down-regulation of bile acid transporter (Asbt) and enhancement of fecal excretion. Conversely, UDCA raised their concentrations by 21.9 % and 34.6 % compared to that exposed solely to PFASs. A strong positive correlation was identified between PFASs serum levels and Asbt expression. This study illuminated PFAS bioaccumulation mechanisms and suggested potential strategies to mitigate the exposure risks.

Network pharmacology-based analysis on the key mechanisms of Yiguanjian acting on chronic hepatitis.

Chronic hepatitis (CH) encompasses a prevalent array of liver conditions that significantly contribute to global morbidity and mortality. Yiguanjian (YGJ) is a classical traditional Chinese medicine with a long history of medicinal as a treatment for CH. Although it has been reported that YGJ can reduce liver inflammation, the intricate mechanism requires further elucidation. We used network pharmacology approaches in this work, such as gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and network-based analysis of protein-protein interactions (PPIs), to clarify the pharmacological constituents, potential therapeutic targets, and YGJ signaling pathways associated with CH. Employing the random walk restart (RWR) algorithm, we identified GNAS, GNB1, CYP2E1, SFTPC, F2, MAPK3, PLG, SRC, HDAC1, and STAT3 as pivotal targets within the PPI network of YGJ-CH. YGJ attenuated liver inflammation and inhibited GNAS/STAT3 signaling in vivo. In vitro, we overexpressed the GNAS gene further to verify the critical role of GNAS in YGJ treatment. Our findings highlight GNAS/STAT3 as a promising therapeutic target for CH, providing a basis and direction for future investigations.

Residue Degradation and Risk Assessment of Difenoconazole and Its Metabolite during Tea Growing, Processing and Brewing by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Determination.

Residue dissipation and risk assessment of difenoconazole and its metabolite difenoconazole-alcohol during tea growing, processing, and brewing was first investigated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The limits of quantification for both difenoconazole and difenoconazole-alcohol were 0.001 mg/kg in fresh tea leaves and tea, and 0.0002 mg/L in tea infusion. In field trials, the dissipation half-lives of difenoconazole in fresh tea leaves was 1.77 days. After spraying, the residues of difenoconazole-alcohol increased and then gradually dissipated like difenoconazole. After 14 days, the dissipation rates of difenoconazole and difenoconazole-alcohol reached 99%. When fresh tea leaves were harvested on different days, the total processing factors (PFs) of difenoconazole and difenoconazole-alcohol for green tea were 0.86-1.05 and 0.78-0.85, respectively, while the total PFs for black tea were 0.83-1.13 and 0.82-1.66, respectively. Metabolism of difenoconazole was accelerated during tea processing. When brewing black tea, the leaching rates (LRs) of difenoconazole and difenoconazole-alcohol were 8.4-17.9% and 31.8-38.9%, respectively, while when brewing green tea, the LRs were 15.4-23.5% and 30.4-50.6%, respectively. The LRs of difenoconazole and difenoconazole-alcohol in black tea were higher than those in green tea. The potential threat to human health for dietary intake of difenoconazole and difenoconazole-alcohol residues from tea consumption is negligible. However, the dietary risk of difenoconazole in fruits and vegetables that are essential for daily diets is concerning, with a risk probability of 158%.

A novel montmorillonite clay-cetylpyridinium chloride material for reducing PFAS leachability and bioavailability from soils.

Soils contaminated by per- and polyfluoroalkyl substances (PFAS) present a significant threat to both ecological and human health. Extensive research efforts are currently underway to develop effective strategies for immobilizing these chemicals in soils. In this study, calcium montmorillonite was modified with cetylpyridinium chloride (CPC-CM) to enhance its electrostatic and hydrophobic interactions with PFAS. CPC-CM exhibited high adsorption for perfluorooctanoate acid (PFOA), perfluorooctane sulfonate (PFOS) and 8:2 fluorotelomer sulfonic acids (8:2 FTSA) across initial concentrations of 50-1000 µg/L, outperforming both the parent CM and L-carnitine modified CM. Soil leaching tests demonstrated the superior immobilization capabilities of the CPC-CM, maintaining an average PFAS leaching rate below 7% after 120-day incubation. In the context of human exposure scenarios, the in vitro bioaccessibility and in vivo bioavailability of PFAS in soils were measured by gastrointestinal extraction and mouse assay. CPC-CM treatment effectively reduced the bioaccessibility (by up to 84%) and bioavailability (by up to 76%) of PFAS in soils. Furthermore, the safety and efficacy of CPC-CM were evaluated using enteric microorganisms of mice. CPC-CM treatment mitigated PFAS-induced changes in the abundance of Bacteroidetes and Firmicutes, thereby reducing PFAS-induced health risks for humans. Overall, CPC-CM synthesized in this study demonstrated superior adsorption performance and application safety, offering a highly promising approach for remediating PFAS-contaminated soil.

A machine learning and experimental-based model for prediction of soil sorption capacity toward phenanthrene.

Sorption by soil is the fundamental basis for environment fate of hydrophobic organic contaminants (HOCs), which varies significantly depending on diverse properties of soils. Therefore, a generalized approach to predict HOC sorption by soils is required. In this study, 488 data points were extracted from references and adopted to develop models for estimating the sorption capacities of phenanthrene in soils using six different machine learning (ML) approaches. The extreme gradient boosting (XGBT) model demonstrated the most favorable performance, achieving a coefficient of determination of 0.91 and root-mean-square errors of 0.24 for the testing dataset. The XGBT model's performance was further demonstrated by comparing with experimental data from batch sorption tests conducted on 20 soil samples collected from 17 provinces of China. The differences between the predicted values and the experimental values were statistically equal to zero (p = 0.14). Leveraging the XBGT model together with soil properties from the Harmonized World Soil Database, the distribution of sorption capacities in Chinese soils was successfully depicted on a national scale. This research is expected to contribute to a deeper understanding of the migration of persistent organic pollutants in terrestrial system. Furthermore, the established model holds implications for more precise and scientific soil environmental management.

Effect of Microplastic Types on the In Vivo Bioavailability of Polychlorinated Biphenyls.

As MPs are released into the soil, various equilibrium statuses are expected. MPs could play roles as a "source," a "cleaner," or a "sink" of HOCs. Three types of MPs (LDPE, PLA, and PS) were selected to study their effect on polychlorinated biphenyl (PCBs) relative bioavailability (RBA) measured by a mouse model. As a "source" of HOCs, exposure to MP-sorbed PCBs resulted in their accumulation in adipose tissue with PCB RBA as 101 ± 6.73% for LDPE, 76.2 ± 19.2% for PLA, and 9.22 ± 2.02% for PS. The addition of 10% MPs in PCB-contaminated soil led to a significant (p < 0.05) reduction in PCB RBA (52.2 ± 16.7%, 49.3 ± 4.85%, and 47.1 ± 5.99% for LDPE, PLA, and PS) compared to control (75.0 ± 4.26%), implying MPs acted as "cleaner" by adsorbing PCBs from the digestive system and reducing PCB accumulation. MPs acted as a "sink" for PCBs in contaminated soil after aging, but the sink effect varied among MP types with more pronounced effect for LDPE than PLA and PS. Therefore, the role played by MPs in bioavailability of HOCs closely depended on the MP types as well as the equilibrium status among MPs, soil, and HOCs.

Influence of dietary bioactive compounds on the bioavailability and excretion of PFOA and its alternative HFPO-TA: Mechanism exploration.

Oral ingestion is considered an important route of human exposure to perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO-TA). Bioactive compounds are widely used as dietary supplements and food additives. However, little is known about the influence of dietary bioactive compounds on the bioavailability of PFOA and HFPO-TA. Here, three dietary bioactive compounds, ß-carotene, quercetin and curcumin, were selected to study their influence on the relative bioavailability (RBA) of PFOA and HFPO-TA in soil using a mouse model. Compared to the control group (68.7 ± 6.27 %), quercetin and curcumin at medium and high doses (20 and 100 mg/kg/d) significantly (p < 0.05) decreased PFOA RBA to 55.2 ± 4.85-56.4 ± 4.57 % and 48.3 ± 5.49-48.6 ± 5.44 %, respectively. Mechanism study showed that medium- and high-dose quercetin as well as high-dose curcumin increased urinary excretion of PFOA by 33.6-35.6 % and 32.2 % through upregulating renal expression of multidrug resistance protein 2 (Mrp2) (1.52-1.63 folds) and Mrp4 (1.26-1.53 folds), thereby reducing PFOA accumulation. In PFOA-treated groups, quercetin at medium and high doses dramatically downregulated the hepatic expression of organic anion transport polypeptides (Oatp1a6, Oatp1b2), organic anion transport proteins (Oat1, Oat2), and fatty acid binding proteins (FABP4, FABP12), while curcumin at medium and high doses inhibited the hepatic expression of Oatp1a6, Oat1 and Oat2. These downregulated genes may reduce the transport of PFOA from blood to liver, and in turn decrease the PFOA RBA. However, ß-carotene, quercetin and curcumin exhibited no significant effect on RBA and excretion of HFPO-TA (p > 0.05). This indicated the different absorption mechanisms between PFOA and HFPO-TA, and further research is warranted. This study provided a novel perspective for establishing environmentally friendly ways to reduce health hazards from per- and polyfluoroalkyl substances (PFASs).

The design and straightforward synthesis of multifunctional DNA microgels for the improved targeted delivery of antitumor drugs.

Multifunctional drug delivery platforms represent ideal approaches to reliably targeting pharmacological agents of interest to the complex tumor microenvironment (TME), yet the complicated synthesis processes, high costs, and toxicities associated with these agents have hindered their clinical application to date. In this study, the properties of the TME are leveraged to develop a multifunctional pNAB/AS DNA microgel that is able to actively target tumors. This microgel is generated by a straightforward one-step free radical precipitation polymerization procedure, exhibiting extremely high drug encapsulation efficiency (∼90%), and is responsive to three environmental stimuli including temperature, reduction, and an acidic pH while showing minimal drug leakage under physiological conditions. Through a synergistic combination of appropriate size and aptamer recognition, this microgel is able to reliably facilitate intratumoral drug accumulation and nuclear drug delivery. Critically, pNAB/AS-Dox treatment is associated with specific antitumor activity in vitro and in vivo while retaining a good biosafety profile and causing lower levels of off-target toxicity as compared to free drug treatment. Together, these findings emphasize the potential value of this multifunctional pNAB/AS DNA microgel as a platform amenable to targeted drug delivery to the TME, providing a foundation for further efforts to readily develop multifunctional drug delivery systems.

Tissue-specific uptake and distribution of liquid crystal monomers (LCMs) in mice.

Increasing evidence indicated that liquid crystal monomers (LCMs) in liquid crystal displays can be released into the environment, and ubiquitously detected in environmental matrices and even human bodies. Yet databases regarding its uptake and distribution in mammals are lacking. In this study, four LCMs (namely 3dFB, 2OdF3B, 2teFT, and 6OCB) with various physiochemical properties and structures were selected as the target compounds. The LCMs were in vivo and in vitro exposed to mice and rat liver microsomes (RLM). LCMs were found in all mouse tissues, including brain. Pharmacokinetics parameters, Cmax-tissue/Cmax-blood, ranged from 27.5 to 214, indicating the preferential deposition of LCMs to tissues rather than blood. The LCMs distributed preferentially to lipophilic tissues, and relative mass contribution of LCMs from liver and adipose was 43-98 %. The physicochemical properties (i.e., Kow, molecular weight, and functional groups) had pronounced effect on distribution and accumulation of LCMs. The 2teFT with the highest Kow and molecular weight showed the relatively higher accumulation potential and half elimination time in all the tissues. The 6OCB containing cyano-group was more accumulative than the fluorinated 3dFB with the comparable Kow. In RLM assays, 2teFT and 6OCB were resistant to metabolic degradation. While 3dFB and 2OdF3B underwent rapid degradation with 93.7 % and 72.4 % being metabolized at 360 min. Findings in this study bear significant implications for the biomonitoring and overall risk evaluation of LCMs.

A new strategy of transforming an ACQ compound into an AIE theranostic system for bacterial imaging and photodynamic antibacterial therapy.

An organic chemical with fluorescence quenching properties [aggregation-caused quenching (ACQ)] may often be transformed by adding functional groups that cause aggregation-induced emission (AIE) to its molecular scaffold. Such structural change techniques, however, sometimes require challenging chemical reactions. SF136 is a type of chalcone, and it is an typical ACQ organic compound. In this study, cationic surfactants like hexadecyltrimethylammonium bromide (CTAB) and polyethyleneimine (PEI) were used to convert the ACQ compound SF136 into an AIE compound without adding any AIE structure units. In comparison to SF136, the SF136-CTAB NPS system not only demonstrated improved bacterial fluorescence imaging capabilities, but also increased photodynamic antibacterial activity, which is connected to its improved targeting and reactive oxygen species (ROS) production abilities. It is a promising theranostic substance against bacteria owing to these enhanced qualities. Other ACQ fluorescent compounds may also benefit from using this approach, broadening the scope of their potential applications.

Clonal integration systemically regulates leaf microstructure of Bouteloua dactyloides interconnected ramets to better adapt to different levels of simulated insect herbivory.

Stolon connection of clonal plants can translocate resources and signalling molecules between interconnected ramets to enhance resistance. Plants are well known to enhance leaf anatomical structure and vein density to respond to insect herbivory. Herbivory signalling molecules are transferred through vascular system to alert distant undamaged leaves, which is called systemic defence induction. Here, we investigated how clonal integration modulates leaf vasculature and anatomical structure of Bouteloua dactyloides ramets to cope with different levels of simulated herbivory. Ramet pairs were subject to six treatments, daughter ramets were exposed to three defoliation levels (0 %, 40 % or 80 % leaf removal) and their stolon connections to mother ramets were either severed or kept intact. Local 40 % defoliation increased vein density and adaxial/abaxial cuticle thickness, decreased leaf width and areolar area of daughter ramets. However, such effects of 80 % defoliation were much smaller. Compared with remote 40 % defoliation, remote 80 % defoliation increased leaf width and areolar area and decreased vein density of interconnected undefoliated mother ramets. Without simulated herbivory, stolon connection negatively affected most leaf microstructural traits of both ramets except from denser veins of mother ramets and more bundle sheath cells of daughter ramets. The negative effect of stolon connection on leaf mechanical structures of daughter ramets was ameliorated in the 40 % defoliation treatment, but not in the 80 % defoliation treatment. Stolon connection increased vein density and decreased areolar area of daughter ramets in the 40 % defoliation treatment. In contrast, stolon connection increased areolar area and decreased bundle sheath cell number of 80 % defoliated daughter ramets. Defoliation signals were transmitted from younger ramets to older ramets to change their leaf biomechanical structure. Clonal integration can adjust leaf microstructure of younger ramets according to the degree of herbivory stress, especially leaf vasculature.

Uptake and translocation of both legacy and emerging per- and polyfluorinated alkyl substances in hydroponic vegetables.

The extensive use of per- and polyfluorinated alkyl substances (PFASs) and their substitutes has resulted in their frequent detections in environmental matrices. However, limited information is known about their uptake into vegetables and health risk through diet, particularly for those emerging alternatives. In this study, a total of 17 PFASs (namely 12 legacy PFASs and 5 of their alternatives) were compared for their accumulation into four staple vegetables (lettuce, Chinese cabbage, chrysanthemum coronarium, and cucumber) in hydroponic system with single PFAS concentration being 10 µg/L, except for 8:2 chlorinated polyfluoroalkyl ether sulfonate (Cl-PFESA) as 0.5 µg/L. The sum concentrations of 17 PFASs in edible parts were in the order of Chinese cabbage leaf (13,456 ng/g) > lettuce leaf (5996 ng/g) > cucumber fruit (4115 ng/g) >chrysanthemum coronarium stem (3999 ng/g). For perfluorooctanoate acid (PFOA) and its alternatives, hexafluoropropylene oxide trimer acid (HFPO-TA) preferentially accumulated in roots than PFOA with root concentration factors being 35.7-99.9. Translocation to edible parts was more remarkable for hexafluoropropylene oxide dimer acid (HFPO-DA) compared with PFOA in lettuce and cucumber. For perfluorooctanesulfonate acid (PFOS) and its alternatives, roots of all the four vegetables were found to more readily accumulate 8:2 Cl-PFESA than PFOS, but 8:2 Cl-PFESA was hardly translocated to the aerial parts. Significantly (p < 0.05) higher edible concentrations of 8:2 and 6:2 fluorotelomer sulfonic acids (FTSA) than that of PFOS were observed for cucumber.

Current perspectives and trend of nanomedicine in cancer: A review and bibliometric analysis.

The limitations of traditional cancer treatments are driving the creation and development of new nanomedicines. At present, with the rapid increase of research on nanomedicine in the field of cancer, there is a lack of intuitive analysis of the development trend, main authors and research hotspots of nanomedicine in the field of cancer, as well as detailed elaboration of possible research hotspots. In this review, data collected from the Web of Science Core Collection database between January 1st, 2000, and December 31st, 2021, were subjected to a bibliometric analysis. The co-authorship, co-citation, and co-occurrence of countries, institutions, authors, literature, and keywords in this subject were examined using VOSviewer, Citespace, and a well-known online bibliometrics platform. We collected 19,654 published papers, China produced the most publications (36.654%, 7204), followed by the United States (29.594%, 5777), and India (7.780%, 1529). An interesting fact is that, despite China having more publications than the United States, the United States still dominates this field, having the highest H-index and the most citations. Acs Nano, Nano Letters, and Biomaterials are the top three academic publications that publish articles on nanomedicine for cancer out of a total of 7580 academic journals. The most significant increases were shown for the keywords "cancer nanomedicine", "tumor microenvironment", "nanoparticles", "prodrug", "targeted nanomedicine", "combination", and "cancer immunotherapy" indicating the promising area of research. Meanwhile, the development prospects and challenges of nanomedicine in cancer are also discussed and provided some solutions to the major obstacles.

Uptake, distribution, and depuration of emerging per- and polyfluoroalkyl substances in mice: Role of gut microbiota.

The bioaccumulation and fate in mammals of hexafluoropropylene oxide trimer acid (HFPO-TA) and hexafluoropropylene oxide dimer acid (HFPO-DA), as major alternatives for perfluorooctanoate (PFOA), have rarely been reported. In addition, the role of gut microbiota was greatly understudied. In this study, the uptake, distribution, and depuration of HFPO-TA, HFPO-DA, and PFOA were investigated by exposure to mice for 14 days, followed by a clearance period of 7 days. The patterns of tissue distribution and depuration kinetics of HFPO-TA and PFOA were similar, but different from HFPO-DA. Liver was the main deposition organ for HFPO-TA and PFOA, making contributions of 58.8 % and 59.1 % to the total mass recovered on day 14. Depuration of HFPO-DA was more rapid than HFPO-TA and PFOA. Approximately 95.3 % of HFPO-DA in liver was eliminated on day 21 compared with day 14. While the clearance rates of HPFO-TA and PFOA were only 6.1 % and 13.9 % on day 21. The comparison between normal and pseudo germ-free mice (GM) was also conducted to investigate the effect of gut microbial on in vivo absorption of the three per- and polyfluoroalkyl substances (PFASs). Significantly higher (p < 0.05) concentrations of all the three PFASs were observed in most organs and tissues of GM compared with NC group. An analysis of gut microbiota showed that the higher absorption of PFASs in GM group may be attributed to the increase of intestinal permeability (as indicated by the decrease of tight junction protein expression), which were induced by the change of lachnospiraceae abundance. The result highlighted the importance of gut microbiota in absorption and health risk evaluation of emerging PFASs.

In vivo relative bioavailability of perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO-TA): Influence of food and mechanisms exploration.

The extensive use of perfluorooctanoic acid (PFOA), and its substitute hexafluoropropylene oxide trimer acid (HFPO-TA) has resulted in their frequent detection in environmental samples. However, little is known of their bioavailability via oral ingestion and the influence of food co-ingestion on absorption. Here, the relative bioavailability (RBA) of PFOA and HFPO-TA in soil was measured using an in vivo mouse model in the presence of food with different nutritional statuses (n = 11). PFOA and HFPO-TA RBA in soil was variable depending on nutrient co-administration, ranging from 29.8-95.5 % and 43.9-68.0 %, respectively. For both PFOA and HFPO-TA, a significantly negative correlation was observed between RBA and protein content in food (r = 0.57-0.72), while a positive correlation was observed with carbohydrate content (r = 0.51-0.57). Mechanistic studies showed that protein in food decreased PFOA and HFPO-TA RBA by down-regulating the expression of fatty acid binding protein 1 (FABP1) and up-regulating the expression of multidrug resistance associated protein 4 (Mrp4) in the liver, which are responsible for the absorption and efflux of PFOA and HFPO-TA. Dietary carbohydrates promoted albumin synthesis and up-regulated FABP1 expression thereby enhancing absorption and increasing PFOA and HFPO-TA RBA. This study provides an insight into potential dietary strategies for reducing exposure to per- and polyfluoroalkyl substances.