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Bisphenol A is an endocrine disruptor associated with hormone synthesis and reproduction alterations. However, the initiating events underpinning these dysfunctions are still unclear. Here, we address the hypothesis that BPA interferes with the highly evolutionary conserved process of mitochondrial cholesterol transport, a crucial step in steroid hormone biosynthesis, by using the model organism C. elegans. We observed that embryonic lethality and germline apoptosis, hallmarks of BPA's reproductive toxicity in C. elegans, are fully rescued by low exogenous cholesterol supplementation. We also observed that increasing BPA concentrations proportionally reduced mitochondrial cholesterol levels. Mutants for strl-1 (ortholog of StAR), but not C41G7.9 (ortholog of TSPO), show reproductive defects similar to BPA's while BPA exposure in a strl-1 background did not worsen these effects. Finally, cholesterol supplementation rescued these defects for all strl-1 genotype/BPA combinations assessed. Together, these results uncover a novel mechanism underlying BPA's germline toxicity through the alteration of cholesterol transport.

We report an effective and environmentally sustainable water treatment approach using enzymes encapsulated in biogenic vault nanoparticles. Manganese peroxidase (MnP), whose stability was remarkably extended by encapsulating into vaults, rapidly catalyzed the biotransformation of endocrine-disrupting compounds, including bisphenol A (BPA), bisphenol F (BPF), and bisphenol AP (BPAP). The vault-encapsulated MnP (vMnP) treatment removed 80-95% of each of the tested bisphenols (BPs) at lower enzyme dosage, while free native MnP (nMnP) only resulted in a 19-36% removal, over a 24-h period. Treatment by vMnP and nMnP resulted in considerable disparities in product species and abundance, which were consistent with the observed changes in the estrogenic activities of BPs. To test if vMnP-catalyzed transformations generated toxic intermediates, we assessed biological hallmarks of BP toxicity, namely, the ability to disrupt reproductive processes. The toxicity of vMnP-treated samples, as measured in the model organism, Caenorhabditis elegans, was dramatically reduced for all three BPs, including the reproductive indicators of BPA exposure such as reduced fertility and increased germ cell death. Collectively, our results indicate that the vMnP system represents an efficient and safe approach for the removal of BPs and promise the development of vault-encapsulated customized enzymes for treating other targeted organic compounds in contaminated waters.

Background: The occurrence and progression of breast cancer are closely linked to copper ion homeostasis. Both copper deficiency and excess can inhibit breast cancer growth, while copper transport systems may contribute to its progression by regulating copper ion transport and the activity of associated proteins. However, a comprehensive review of the roles and applications of copper transport systems in breast cancer remains limited. In this study, we summarize the workflow of copper transport systems and the dual role of copper in cancer, highlighting the contributions of specific members of the copper transport system to breast cancer. Methods: A comprehensive search of the PubMed database was conducted to identify articles published over the past 30 years that focus on the relationship between copper transport system members and breast cancer. The findings were synthesized to elucidate the roles and mechanisms of these transporters in the onset and progression of breast cancer. Results: We identified 13 members of the copper transport system associated with the occurrence, progression, and mortality of breast cancer, including SLC31A1, DMT1, ATP7A, ATP7B, MTs, GSH, ATOX1, CCS, COX17, SCO1, SCO2, and COX11. Our findings revealed that, apart from STEAP, the remaining 12 members were overexpressed in breast cancer. These members influence the onset, progression, and cell death of breast cancer by modulating biological pathways such as intracellular copper ion levels and ROS. Notably, we observed for the first time that depletion of the copper storage protein GSH leads to increased copper ion accumulation, resulting in cuproptosis in breast cancer cells. Conclusion: By integrating the members of the copper transport system in breast cancer, we offer novel insights for the treatment of breast cancer and copper‐related therapies. [ABSTRACT FROM AUTHOR]

Introduction: Chemo-immunotherapy based on inducing tumor immunogenic cell death (ICD)with chemotherapy drugs has filled the gaps between traditional chemotherapy and immunotherapy. It is verified that paclitaxel (PTX) can induce breast tumor ICD. From this basis, a kind of nanoparticle that can efficiently deliver different drug components simultaneously is constructed. The purpose of this study is for the sake of exploring the scheme of chemotherapy-induced ICD combined with other immunotherapy to enhance tumor immunogenicity and inhibit the growth, metastasis, and recurrence of breast tumors, so as to provide a research basis for solving the tough problem of breast cancer treatment. Methods: Nanomedicine loaded with PTX, small interference RNA that suppresses CD47 expression (CD47siRNA, siCD47), and immunomodulator R848 were prepared by the double emulsification method. The hydrodynamic diameter and zeta potential of NP/PTX/siCD47/R848 were characterized. Established the tumor-bearing mice model of mouse breast cancer cell line (4T1) in situ and observed the effect of intravenous injection of NP/PTX/siCD47/R848 on the growth of 4T1 tumor in situ. Flow cytometry was used to detect the effect of drugs on tumor immune cells. Results: NP/PTX/siCD47/R848 nano-drug with tumor therapeutic potential were successfully prepared by double emulsification method, with particle size of 121.5 ± 4.5 nm and surface potential of 36.1 ± 2.5 mV. The calreticulin on the surface of cell membrane and extracellular ATP or HMGB1 of 4T1 cells increased through treatment with NPs. NP/PTX-treated tumor cells could cause activation of BMDCs and BMDMs. After intravenous injection, NP/PTX could quickly reach the tumor site and accumulate for 24 h. The weight and volume of tumor in situ in the breast cancer model mice injected with nanomedicine through the tail vein were significantly lower than those in the PBS group. The ratio of CD8+/CD4+ T cells in the tumor microenvironment and the percentage of dendritic cells in peripheral blood increased significantly in breast cancer model mice injected with nano-drugs through the tail vein. Discussion: Briefly, the chemotherapeutic drug paclitaxel can induce breast cancer to induce ICD. The nanomedicine which can deliver PTX, CD47siRNA, and R848 at the same time was prepared by double emulsification. NP/PTX/siCD47/R848 nano-drug can be enriched in the tumor site. The experiment of 4T1 cell tumor-bearing mice shows that the nano-drug can enhance tumor immunogenicity and inhibit breast tumor growth, which provides a new scheme for breast cancer treatment. (Graphical abstract) Intravenous injection of PTX-loaded nanomedicine based on PEG-PLGA causes immunogenic death of tumor cells and simultaneously reduces tumor cell immune escape, promotes macrophage polarization towards MI subtypes, and effectively activates DCs, thereby enhancing anti-tumor immunity. [ABSTRACT FROM AUTHOR]

The feasibility of industrial waste fly ash as an alternative fluxing agent for silica in carbothermal reduction of medium-low-grade phosphate ore was studied in this paper. With a series of single-factor experiments, the reduction rate of phosphate rock under different reaction temperature, reaction time, particle size, carbon excess coefficient, and silicon–calcium molar ratio was investigated with silica and fly ash as fluxing agents. Higher reduction rates were obtained with fly ash fluxing instead of silica. The optimal conditions were derived as: reaction temperature 1,300°C, reaction time 75 min, particle size 48–75 µm, carbon excess coefficient 1.2, and silicon–calcium molar ratio 1.2. The optimized process condition was verified with other two different phosphate rocks and it was proved universally. The apparent kinetics analyses demonstrated that the activation energy of fly ash fluxing is reduced by 31.57 kJ/mol as compared with that of silica. The mechanism of better fluxing effect by fly ash may be ascribed to the fact that the products formed within fly ash increase the amount of liquid phase in the reaction system and promote reduction reaction. Preliminary feasibility about the recycling of industrial waste fly ash in thermal phosphoric acid industry was elucidated in the paper.

Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures.

The effects of particle size on the apparent kinetics of carbothermal reduction process of phosphate rock were studied by non-isothermal thermogravimetric analyses. Phosphate rock of various particle size was reacted with coke and silica under high purity argon atmosphere. The apparent kinetic model and parameters of carbothermal reduction reaction of phosphate rock with different particle sizes were derived by combination of model-free (Flynn–Wall–Ozawa, Kissinger–Akahira–Sunose, Tang, Starink) and model-fitting (Coats-Redfern, Master-plots) methods. The results showed that the obtained apparent activation energy of reaction reduces from 371.74 kJ/mol to 321.11 kJ/mol as the particle size of phosphate rock decreasing from 100–150 μm to 38–48 μm. The reaction apparent kinetics was found to follow shrinking-core model and the conversion degree function equation is G(α)=1−(1−α)12G\left( \alpha \right) = 1 - {\left( {1 - \alpha } \right)^{{1 \over 2}}} (α is conversion degree and G(α) is integral form of conversion degree function).

The comprehensive identification and mechanistic analysis of reproductive toxicants constitutes one of the major hurdles in the toxicological assessment of chemicals originating from the large number of chemicals to be tested and the difficulty in examining germ cells at various stages of their development. We previously described the development of an assay in the roundworm Caenorhabditis elegans that allows the detection of chemicals bearing aneugenic activity and that could be used for the detection of germline toxicity. We present here new evidence for the reproductive toxicity of three pesticides identified in our germline toxicity assay: Maneb, Diazinon and Fenarimol. We show that all three pesticides cause an acute germline nuclear loss in exposed nematodes in a dose-dependent fashion. The loss of germline nuclei coincides with the meiotic stage of pachytene during Prophase I and is dependent on the germline apoptotic machinery suggesting activation of a meiotic checkpoint. Further investigation revealed a profound dysregulation of the meiotic program revealed by (1) an alteration of the kinetics of double strand repair, (2) the disruption of the process of chromosome morphogenesis at the end of Prophase I and (3) the reorganization of the meiotic differentiation gradient inherent to the C. elegans germline following exposure to Maneb and Diazinon. These defects correlate with a significant increase in embryonic lethality and a corresponding decrease in the number of progeny. These results therefore provide strong evidence for the reproductive toxicity of Maneb, Diazinon and Fenarimol rooted in the alteration of early steps of germ cell differentiation.

Introduction Congenital heart disease (CHD) occurs in ~1% of newborns in the United States. (1,2) This disease can arise from many distinct etiologies that elicit diverse cellular and molecular responses [...], Objectives: We evaluated the effects of Cd on the different stages (mesoderm, cardiac induction, cardiac function) of cardiac development using an early embryo development in vitro model and two- or three-dimensional (2- or 3D) cardiomyocyte and cardiac organoid formation models mimicking early cardiac development. Methods: Embryonic stem cells (ESCs) form 3D aggregates, called embryoid bodies, that recapitulate events involved with early embryogenesis (e.g., germ layer formation). This model was used for early germ layer formation and signaling pathway identification. The 2D cardiomyocyte differentiation from the NKX2-[5.sup.eGFP/w] human ESCs model was used to explore the effects of Cd exposure on cardiomyocyte formation and to model mesoderm differentiation and cardiac induction, allowing us to explore different developmental windows of Cd toxicity. The 3D cardiac organoid model was used in evaluating the effects of Cd exposure on contractility and cardiac development. Results: Cd (0.6 [micro]M; 110ppb) lowered the differentiation of embryoid bodies to mesoderm via suppression of Wnt/[beta]-catenin-signaling pathways. During early mesoderm induction, the mesoderm-associated transcription factors MESP1 and EOMES showed a transient up- regulation, which decreased later in the cardiac induction stage. Cd (0.15 [micro]M) lowered mesoderm formation and cardiac induction through suppression of the transcription factors and mesoderm marker genes HAND1, SNAI2, HOPX, and the cardiac-specific genes NKX2-5, GATA4, troponin T, and alpha-actinin. In addition, Cd-induced histone modifications for both gene activation (H3K4me3) and repression (H3K27me3), which play vital roles in regulating mesoderm commitment markers. The effects of Cd inhibition on cardiomyocyte differentiation were confirmed in 3D cardiac organoids. Discussion: In conclusion, using a human ESC-derived 2D/3D in vitro differentiation model system and cardiac organoids, we demonstrated that low-dose Cd suppressed mesoderm formation through mesoderm gene histone modification, thus inhibiting cardiomyocyte differentiation and cardiac induction. The studies provide valuable insights into cellular events and molecular mechanisms associated with Cd- induced congenital heart disease. https://doi.org/10.1289/EHP11208

Dopamine (DA) is a crucial neurotransmitter in the central nervous system (CNS) of human and multicellular animal brains. In this paper, we report for the first time the synthesis of carbon black (C)/phosphotungstic acid (PWA) composites by doping PWA on carbon black nanoparticles by impregnation method. The synthesized materials were characterized using high‐resolution scanning electron microscopy (SEM), X‐ray diffraction spectroscopy (XRD) and Fourier transform infrared spectroscopy (FT‐IR). Glassy carbon electrodes (GCE) modified by C/PWA composites were used to detect dopamine. The electrochemical redox behavior of DA was studied with cyclic voltammetry (CV). Under optimized conditions, DA was detected by differential pulse voltammetry (DPV) and the calibration plot showed linearity (R2=0.9988) over the range of DA concentrations of 10 μM‐600 μM with a detection limit of 0.1 μM. The sensor's capability to detect DA in commercial DA injections in real time has been successfully demonstrated. [ABSTRACT FROM AUTHOR]