peer reviewed | Metconazole (MEZ), a chiral triazole fungicide, produces enantioselective adverse effects in non-target organisms. Among MEZ's isomers, cis-MEZ displays robust antimicrobial properties. Evaluating MEZ and cis-MEZ's toxicity may mitigate fungicide usage and safeguard non-target organisms. Our study evaluated the toxicity of MEZ and its cis-isomers at concentrations of 0.02, 0.2, 2, and 4 mg L−1. We report stereoselectivity and severe cardiovascular defects in zebrafish, including pericardial oedema, decreased heart rate, increased sinus venous and bulbous arteries distances, intersegmental vessel defects, and altered cardiovascular development genes (hand2, gata4, nkx2.5, tbx5, vmhc, amhc, dll4, vegfaa, and vegfc). Further, MEZ significantly increased oxidative stress and apoptosis in zebrafish, primarily in the cardiac region. Isoquercetin, an antioxidant found in plants, partially mitigates MEZ-induced cardiac defects. Furthermore, MEZ upregulated the Wnt/β-catenin pathway genes (wnt3, β-catenin, axin2, and gsk-3β) and β-catenin protein expression. Inhibitor of Wnt Response-1 (IWR-1) rescued MEZ-induced cardiotoxicity. Our findings highlight oxidative stress, altered cardiovascular development genes, and upregulated Wnt/β-catenin signaling as contributors to cardiovascular toxicity in response to MEZ and cis-MEZ treatments. Importantly, 1R,5S-MEZ exhibited greater cardiotoxicity than 1S,5R-MEZ. Thus, our study provides a comprehensive understanding of cis-MEZ's cardiovascular toxicity in aquatic life. © 2024 Elsevier Ltd

Particulate matter with aerodynamic diameter not larger than 2.5 μm (PM₂.₅) escalated the risk of respiratory diseases. Mitochondrial dysfunction may play a pivotal role in PM₂.₅-induced airway injury. However, the potential effect of PM₂.₅ on mitochondrial permeability transition pore (mPTP)-related airway injury is still unknown. This study aimed to investigate the role of mPTP in PM₂.₅-induced mitochondrial dysfunction in airway epithelial cells in vitro. PM₂.₅ significantly reduced cell viability and caused apoptosis in BEAS-2B cells. We also found PM₂.₅ caused cellular and mitochondrial morphological alterations, evidenced by the disappearance of mitochondrial cristae, mitochondrial swelling, and the rupture of the outer mitochondrial membrane. PM₂.₅ induced mPTP opening via upregulation of voltage-dependent anion-selective channel (VDAC), leading to deprivation of mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) generation and intracellular calcium level. PM₂.₅ suppressed mitochondrial respiratory function by reducing basal and maximal respiration, and ATP production. The mPTP targeting compounds cyclosporin A [CsA; a potent inhibitor of cyclophilin D (CypD)] and VBIT-12 (a selective VDAC1 inhibitor) significantly inhibited PM₂.₅-induced mPTP opening and apoptosis, and preserved mitochondrial function by restoring mitochondrial membrane potential, reducing mitochondrial ROS generation and intracellular calcium content, and maintaining mitochondrial respiration function. Our data further demonstrated that PM₂.₅ caused reduction in nuclear expressions of PPARγ and PGC-1α, which were reversed in the presence of CsA. These findings suggest that mPTP might be a potential therapeutic target in the treatment of PM₂.₅-induced airway injury.

Paraquat, a widely used herbicide, causes environmental pollution, and liver injury in humans and animals. As a natural compound in fruits, ellagic acid (EA) shows anti-inflammatory and antioxidant effects. This study examines the beneficial effects of dietary EA against the paraquat-induced hepatic injury and further explores the underlying molecular mechanisms using a piglet model. Post-weaning piglets are fed basal diet supplemented with 50 mg/kg, 100 mg/kg, or 200 mg/kg EA for 3 weeks. At week 2, hepatic injury is induced by 4 mg/kg paraquat followed by 7 days recovery. EA supplementation significantly mitigates paraquat-induced hepatic fibrosis, steatosis, and high apoptotic rate. In agreement, EA supplementation reduces serum pro-inflammatory levels, ameliorates inflammatory cells infiltration into hepatic tissue, which are associated with suppressed NF-κB signaling during paraquat exposure. In addition, EA supplementation significantly improves activities of antioxidative enzymes which were correlated with activated Nrf2/Keap 1 signaling during paraquat exposure. Furthermore, EA supplementation restores cecal microbial community during paraquat exposure. The protective effect of EA is strongly linked with increased relative abundance of Lactobacillus reuteri and Lactobacillus amylovorus. Taken together, EA supplementation effectively reduced the occurrence of hepatic oxidative damage and inflammation induced by paraquat through modulating cecal microbial communities, which provides a novel nutritional therapeutic strategy for hepatic injury.

Endocrine-disrupting chemicals (EDCs) are ubiquitous in daily life, but their harmful effects on the human body have not been fully explored. Recent studies have shown that EDCs exposure could lead to infertility, menstrual disorder and menopause, resulting in subsequent effects on female health. Therefore, it is of great significance to clarify and summarize the impacts of EDCs on ovarian aging for explaining the etiology of ovarian aging and maintaining female reproductive health. Here in this review, we focused on the impacts of ten typical environmental contaminants on the progression of ovarian aging during adult exposure, including epidemiological data in humans and experimental models in rodents, with their clinical phenotypes and underlying mechanisms. We found that both persistent (polychlorinated biphenyls, perfluoroalkyl and polyfluoroalkyl substances) and non-persistent (phthalates) EDCs exposure could increase an overall risk of ovarian aging, leading to the diminish of ovarian reserve, decline of fertility or fecundity, irregularity of the menstrual cycle and an earlier age at menopause, and/or premature ovarian insufficiency/failure in epidemiological studies. Among these, the loss of follicles can also be validated in experimental studies of some EDCs, such as BPA, phthalates, parabens and PCBs. The underlying mechanisms may involve the impaired ovarian follicular development by altering receptor-mediated pro-apoptotic pathways, inducing signal transduction and cell cycle arrest and epigenetic modification. However, there were inconsistent results in the impacts on fertility/fecundity, menstrual/estrous cycle and hormone changes response to different EDCs, and differences between human and animal studies. Our review summarizes the current state of knowledge on ovarian disrupters, highlights their risks to ovarian aging and identifies knowledge gaps in humans and animals. We therefore propose that females adopt healthy lifestyle changes to minimize their exposure to both persistent and non-persistent chemicals, that have the potential damage to their reproductive function.

Monobutyl phthalate (MBP) is the main metabolite of dibutyl phthalate (DBP) in vivo. MBP has a stable structure, can continuously accumulate in living organisms, and has the potentially to harm animal and human reproductive function. In the ovarian follicle microenvironment, MBP may lead to defects in follicular development and steroid production, abnormal meiotic maturation, impaired ovarian function and other reproductive deficits. In this study, SMART-seq was used to investigate the effects of MBP exposure on the in vitro maturation (IVM) and development of porcine oocytes. The results showed that differentially expressed genes after MBP exposure were enriched in the biological processes cytoskeleton, cell apoptosis, endoplasmic reticulum (ER) and mitochondria. Glycine (Gly) improved the developmental potential of porcine oocytes by regulating mitochondrial and ER function. The effect of Gly in protecting oocytes against MBP-induced damage was studied. The results showed that the addition of Gly significantly decreased the rate of MBP-induced spindle abnormalities, decreased the frequency of MBP-induced mitochondria-associated ER membrane (MAM) interactions, and downregulated the protein and gene expression of the linkage molecules Mitofusin 1 (MFN1) and Mitofusin 2 (MFN2) in the MAM. Additionally, treatment with Gly restored the distribution of the 1,4,5-triphosphate receptor 1 (IP₃R1) and voltage-dependent anion channel 1 (VDAC1), further decreasing the intracellular free calcium concentration ([Ca²⁺]ᵢ) levels and mitochondrial Ca²⁺ ([Ca²⁺]ₘ) , increasing the ER Ca²⁺ ([Ca²⁺]ER) levels, and thus significantly increasing the ER levels and mitochondrial membrane potential (ΔΨ m). Gly also decreased the levels of reactive oxygen species (ROS) and increased the levels of Glutathione (GSH), oocyte apoptosis-related indicators (Caspase-3 activity and Annexin V) and oocyte apoptosis-related genes (BAX, Caspase 3 and AIFM1). Our results suggest that Gly can ameliorate microtubule cytoskeleton abnormalities and improve oocyte maturation by reducing the defective mitochondrial–ER interactions caused by MBP exposure in vitro.

Contamination of phthalate ester plasticizers threatens the wildlife as well as human health. To evaluate the developmental toxicity of commonly used phthalate esters and emerging alternatives, the frog embryo teratogenesis assay-Xenopus (FETAX) was conducted for dibutyl-phthalate (DBP), benzyl-butyl-phthalate (BBP), dioctyl-terephthalate (DOTP), di(2-propylheptyl)-phthalate (DPHP), diisononyl-phthalate (DINP), diisodecyl-phthalate (DIDP), diethyl hexyl cyclohexane (DEHCH), and diisononyl-cyclohexane-1,2-dicarboxylate (DINCH). The 96-hrs LC₅₀ for DBP, BBP, DOTP, DIDP, DINCH, DINP, DPHP, and DEHCH were 18.3, 20.1, 588.7, 718.0, 837.5, 859.3, 899.0, and 899.0 mg/L, respectively. The 96-hrs EC₅₀ of developmental abnormality of DBP, BBP, DPHP, DOTP, DINP, DEHCH, DINCH, and DIDP were 7.5, 18.2, 645.1, 653.6, 664.4, 745.6, 813.7, and 944.5 mg/L, respectively. The lowest observed effective concentration for embryonic survival, malformation, and growth was DINP, DBP, BBP, DIDP, DPHP, DINCH, DEHCH, and DOTP in increasing order. In tadpoles, DBP, BBP, DEHCH, DINP, and DIDP caused inositol-requiring enzyme 1 or protein kinase R-like endoplasmic reticulum kinase pathway endoplasmic reticulum stress (ERS) in order, and BBP, DBP, DOTP, DPHP, DINP, and DIDP caused long term ERS-related apoptosis or mitochondrial apoptosis in order. Together, in Xenopus embryos, the developmental toxicity and the cellular stress-inducing potential of tested plasticizers were DEHCH, DINCH, DPHP, DIDP, DINP, DOTP, BBP, and DBP in increasing order. In consideration of public as well as environmental health this information would be helpful for industrial choice of phthalate ester plasticizers and their alternatives.

Particulate matter with a diameter of less than 2.5 μm or PM2.5 is recognized worldwide as a cause of public health problems, mainly associated with respiratory and cardiovascular diseases. There is accumulating evidence to show that exposure to PM2.5 has a crucial causative role in various neurological disorders, the main ones being dementia and Alzheimer's disease (AD). PM2.5 can activate glial and microglial activity, resulting in neuroinflammation, increased intracellular ROS production, and ultimately neuronal apoptosis. PM2.5 also causes the alteration of neuronal morphology and synaptic changes and increases AD biomarkers, including amyloid-beta and hyperphosphorylated-tau, as well as raising the levels of enzymes involved in the amyloidogenic pathway. Clinical trials have highlighted the correlation between exposure to PM2.5, dementia, and AD diagnosis. This correlation is also displayed by concordant evidence from animal models, as indicated by increased AD biomarkers in cerebrospinal fluid and markers of vascular injury. Blood-brain barrier disruption is another aggravated phenomenon demonstrated in people at risk who are exposed to PM2.5. This review summarizes and discusses studies from in vitro, in vivo, and clinical studies on causative relationships of PM2.5 exposure to AD-related neuropathology. Conflicting data are also examined in order to determine the actual association between ambient air pollution and neurodegenerative diseases.

Cadmium (Cd), as an environmental pollutant, can lead to nephrotoxicity. However, its nephrotoxicological mechanisms have not been fully elucidated. In this study, Cd (1.5 mg/kg body weight, gavaged for 4 weeks) was found to induce the renal damage in mice, based on indicators including Cd concentration, kidney index, serum creatinine and blood urea nitrogen levels, pro-inflammatory cytokines and their mRNA expressions, levels of Bcl-2, Bax and caspase9, and histopathological changes of the kidneys. Furthermore, Cd-caused detrimental changes through inducing inflammation and apoptosis via the miR-34a/Sirt1/p53 axis. This is the first report on the role of miR-34a/Sirt1/p53 axis in regulating Cd-caused apoptosis and nephrotoxicity in mice. The findings obtained in this study provide new insights into miRNA-based regulation of heavy metal induced-nephrotoxicity.

Zearalenone (ZEA) is an estrogenic toxin produced by Fusarium strains, that is widely present in crops, and endangers the reproductive system of animals. Tannic acid (TA) is a natural polyphenolic substance that is widespread in the roots, stems, and leaves of plants, and has special pharmacological activity. This study was designed to investigate the therapeutic effect of TA on ZEA-induced ovarian damage in mice and to explore the molecular mechanism involved. Ninety healthy Kunming female mice were divided into six equal groups. All the groups but the control group were administered daily with ZEA [10 mg/kg body weight (bw)] orally, for 7 days, to induce damage to the reproductive system. Some groups were also administered with TA (50, 100, and 200 mg/bw) for 7 days. Mice were euthanized 24 h later to allow for collection of serum and ovaries. TA can effectively alleviate the appearance of congestion and redness of the ovary, caused by ZEA, and increase the number of healthy growing follicles. Moreover, the estrogen content and the levels of MDA and ROS in the ovaries can be effectively reduced by TA. It can also reduce the apoptosis of ovarian cells, decreases the protein expression of the estrogen receptor, Fas, Fasl, caspase-3, caspase-8, caspase-9, and Bax, and increases the protein expression of Bcl-2. Our study indicates that TA reduces the strong estrogen and oxidative damage induced by ZEA, and these therapeutic effects may be partially mediated by the death receptor and mitochondrial apoptosis signaling pathway.

Quantum dots (QDs) are nanoparticles of inorganic semiconductors and have great promise in various applications. Many studies have indicated that mitochondria are the main organelles for the distribution and toxic effects of QDs. However, the underlying mechanism of QDs interacting with mitochondria and affecting their function is unknown. Here, we report the mechanism of toxic effects of 3-mercaptopropionic acid (MPA)-capped CdTe QDs on mitochondria. Human liver carcinoma (HepG2) cells were exposed to 25, 50 and 100 μmol/L of MPA-capped CdTe QDs. The results indicated that MPA-capped CdTe QDs inhibited HepG2 cell proliferation and increased the extracellular release of LDH in a concentration-dependent manner. Furthermore, MPA-capped CdTe QDs caused reactive oxygen species (ROS) generation and cell damage through intrinsic apoptotic pathway. MPA-capped CdTe QDs can also lead to the destruction of mitochondrial cristae, elevation of intracellular Ca²⁺ levels, decreased mitochondrial transmembrane potential and ATP production. Finally, we showed that MPA-capped CdTe QDs inhibited mitochondrial fission, mitochondrial inner membrane fusion and mitophagy. Taken together, MPA-capped CdTe QDs induced significant mitochondrial dysfunction, which may be caused by imbalanced mitochondrial fission/fusion and mitophagy inhibition. These findings provide insights into the regulatory mechanisms involved in MPA-capped CdTe QDs-induced mitochondrial dysfunction.