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.

Oxytetracycline (OTC) and Cu are prevalent in aquatic ecosystems and their pollution are issues of serious concern. The present working hypothesis is that the toxicity of Cu and OTC mixture on physiological activity of fish was different from single OTC and Cu alone. The present study indicated that, compared to single OTC or Cu alone, Cu+OTC mixture reduced growth performance and feed utilization of grass carp, escalated the contents of Cu, OTC and TG, increased lipogenesis, induced oxidative stress, damaged the mitochondrial structure and functions and inhibited the lipolysis in the liver tissues and hepatocytes of grass carp. Cu+OTC co-treatment significantly increased the mRNA abundances and protein expression of Nrf2. Moreover, we found that Cu+OTC mixture-induced oxidative stress promoted Nrf2 recruitment to the SREBP-1 promoter and increased SREBP-1-mediated lipogenesis; Nrf2 sited at the crossroads of oxidative stress and lipid metabolism, and mediated the regulation of oxidative stress and lipid metabolism. Our findings clearly indicated that OTC and Cu mixture differed in environmental risks from single antibiotic or metal element itself, and thus posed different toxicological responses to aquatic animals. Moreover, our findings suggested that Nrf2 functioned as an important antioxidant regulator linking oxidative stress to lipogenic metabolism, and thus elucidated a novel regulatory mechanism for lipid metabolism.

N6-methyladenosine (m⁶A) mRNA methylation plays a role in various brain functions. Exposure to chronic constant light (CCL) has been reported to impair cognition, yet whether the underlying mechanism involves m⁶A remains unknown. In this study, mice exposed to CCL for 3 weeks show impaired cognitive behavior, which was associated with increased m⁶A level in hippocampus. Accordingly, the m⁶A demethylase FTO was inhibited while the methyltransferases METTL3, METTL14 and WTAP, as well as the reader protein YTHDF2, were elevated in the hippocampus of CCL-exposed mice. CCL exposure significantly activated hippocampal expression of circadian regulator cryptochrome 1 and 2 (CRY1 and 2). Meanwhile, hippocampal neurogenesis was impaired with suppression of BDNF/TrκB/ERK pathway. To further delineate the signaling pathway and the role of m⁶A, we altered the expression of CRY1/2 in hippocampus neuron cells. CRY1/2 overexpression inhibited FTO and increased m⁶A levels, while CRY1/2 knockdown led to opposite results. Luciferase reporter analysis further confirmed CRY1/2-induced FTO suppression. Furthermore, FTO knockdown increased m⁶A on 3′UTR of TrκB mRNA, and decreased TrκB mRNA stability and TrκB protein expression, in a YTHDF2-dependent manner. These results indicate that CCL-activated CRY1/2 causes transcriptional inhibition of FTO, which suppresses TrκB expression in hippocampus via m⁶A-dependent post-transcriptional regulation and contributes to impaired cognitive behavior in mice exposed to constant light.

Chemicals such as triclosan are a concern because of their presence on daily products (soap, deodorant, hand sanitizers …), consequently this compound has an ubiquitous presence in the environment. Little is known about the effect of this bactericide on aquatic life. The aim of this study is to analyze triclosan exposure (24 h) to an in vitro model, zebrafish hepatocytes cell line (ZF-L), if it can be cytotoxic (mitochondrial activity, membrane stability and apoptosis) and if can activate ATP-binding cassette (ABC) proteins (activity, expression and protein/compound affinity). Triclosan was cytotoxic to hepatocytes when exposed to concentrations (1–4 mg/L). The results showed impaired mitochondria function, as well, plasma membrane rupture and an increase of apoptotic cells. We observed an ABC proteins activity inhibition in cells exposed to 0.5 and 1 mg/L. When ABCBs and ABCC2 proteins expression were analyzed, there was an increase of protein expression in both ABC proteins families on cells exposed to 1 mg/L of triclosan. On molecular docking results, triclosan and the fluorescent used as substrate (rhodamine) presented high affinity with all ABC proteins family tested, showing a greater affinity with ABCC2. In conclusion, this study showed that triclosan can be cytotoxic to ZF-L. Molecular docking indicated high affinity between triclosan and the tested pumps.

Exposure to environmental endocrine disrupting chemicals (EDCs) is highly suspected in prostate carcinogenesis. Though, estrogenicity is the most studied behavior of EDCs, the androgenic potential of most of the EDCs remains elusive. This study investigates the androgen mimicking potential of some common EDCs and their effect in androgen-dependent prostate cancer (LNCaP) cells. Based on the In silico interaction study, all the 8 EDCs tested were found to interact with androgen receptor with different binding energies. Further, the luciferase reporter activity confirmed the androgen mimicking potential of 4 EDCs namely benzo[a]pyrene, dichlorvos, genistein and β-endosulfan. Whereas, aldrin, malathion, tebuconazole and DDT were reported as antiandrogenic in luciferase reporter activity assay. Next, the nanomolar concentration of androgen mimicking EDCs (benzo[a]pyrene, dichlorvos, genistein and β-endosulfan) significantly enhanced the expression of AR protein and subsequent nuclear translocation in LNCaP cells. Our In silico studies further demonstrated that androgenic EDCs also bind with epigenetic regulatory enzymes namely DNMT1 and HDAC1. Moreover, exposure to these EDCs enhanced the protein expression of DNMT1 and HDAC1 in LNCaP cells. These observations suggest that EDCs may regulate proliferation in androgen sensitive LNCaP cells by acting as androgen mimicking ligands for AR signaling as well as by regulating epigenetic machinery. Both androgenic potential and epigenetic modulatory effects of EDCs may underlie the development and growth of prostate cancer.

Cadmium (Cd) is a harmful heavy metal that can cause many health problems, while selenium (Se) is an essential nutrient for organisms that can protect them from heavy metal-induced damage. To explore the effects of Se on Cd-induced mitophagy in the liver, forty 3-month-old New Zealand white rabbits (2–2.5 kg), half male and half female, were randomly divided into four groups: the Control group, the Se (0.5 mg/kg body weight (BW)) group, the Cd (1 mg/kg BW) group and the Se+Cd group. After 30 days, the toxicity from Cd in the liver was assessed in terms of the nuclear xenobiotic receptor (NXR) response, oxidative stress and mitophagy. It was found that Cd decreased the activities of CYP450 enzymes and antioxidant enzymes and increased the contents of malondialdehyde (MDA) and hydrogen peroxide (H₂O₂) and also increased the consumption of reduced glutathione (GSH). Moreover, the mRNA levels of NXRs (CAR, PXR, AHR and Nrf2), some mitochondrial function factors (PGC-1α, Sirt1, Sirt3, Nrf1 and TFAM) and mitochondrial fusion factors (Mfn1, Mfn2 and OPA1) were downregulated, but the mRNA levels of other mitochondrial function factors (VDAC1, Cyt C and PRDX3), mitochondrial fission factors (Fis1 and MFF) and those in the PINK1/Parkin-mediated mitophagy pathway (p62, Bnip3 and LC3) were upregulated under Cd exposure. The protein expression levels of Nrf2, SOD2, PGC-1α, PINK1 and Parkin were consistent with the mRNA expression levels in the Cd group. Se alleviated the changes in the abovementioned factors induced by Cd. In conclusion, the results indicate that Cd can cause oxidative stress in rabbit livers by inhibiting NXRs and the antioxidation response leading to mitophagy, and these harmful changes caused by Cd can be alleviated by Se.

Cadmium (Cd) is a heavy metal toxicant as a common pollutant derived from many agricultural and industrial sources. The absorption of Cd takes place primarily through Cd-contaminated food and water and, to a significant extent, via inhalation of Cd-contaminated air and cigarette smoking. Epidemiological data suggest that occupational or environmental exposure to Cd increases the health risk for osteoporosis and spontaneous fracture such as itai-itai disease. However, the direct effects and underlying mechanism(s) of Cd exposure on bone damage are largely unknown. We used primary bone marrow-derived mesenchymal stromal cells (BMMSCs) and found that Cd significantly induced BMMSC cellular senescence through over-activation of NF-κB signaling pathway. Increased cell senescence was determined by production of senescence-associated secretory phenotype (SASP), cell cycle arrest and upregulation of p21/p53/p16ᴵᴺᴷ⁴ᵃ protein expression. Additionally, Cd impaired osteogenic differentiation and increased adipogenesis of BMMSCs, and significantly induced cellular senescence-associated defects such as mitochondrial dysfunction and DNA damage. Sprague-Dawley (SD) rats were chronically exposed to Cd to verify that Cd significantly increased adipocyte number, and decreased mineralization tissues of bone marrow in vivo. Interestingly, we observed that Cd exposure remarkably retarded bone repair and regeneration after operation of skull defect. Notably, pretreatment of melatonin is able to partially prevent Cd-induced some senescence-associated defects of BMMSCs including mitochondrial dysfunction and DNA damage. Although Cd activated mammalian target of rapamycin (mTOR) pathway, rapamycin only partially ameliorated Cd-induced cell apoptosis rather than cellular senescence phenotypes of BMMSCs. In addition, a selective NF-κB inhibitor moderately alleviated Cd-caused the senescence-related defects of the BMMSCs. The study shed light on the action and mechanism of Cd on osteoporosis and bone ageing, and may provide a novel option to ameliorate the harmful effects of Cd exposure.

Trichloropropyl phosphate (TCPP) is a halogenated organophosphate ester that is widely used as flame retardants and plasticizers. In this study, gender-specific accumulation and responses in mussel Mytilus galloprovincialis to TCPP exposure were focused and highlighted. After TCPP (100 nmol L⁻¹) exposure for 42 days, male mussels showed similar average bioaccumulation (37.14 ± 6.09 nmol g⁻¹ fat weight (fw)) of TCPP with that in female mussels (32.28 ± 4.49 nmol g⁻¹ fw). Proteomic analysis identified 219 differentially expressed proteins (DEPs) between male and female mussels in control group. There were 52 and 54 DEPs induced by TCPP in male and female mussels, respectively. Interestingly, gender-specific DEPs included 37 and 41 DEPs induced by TCPP in male and female mussels, respectively. The proteomic differences between male and female mussels were related to protein synthesis and degradation, energy metabolism, and functions of cytoskeleton and motor proteins. TCPP influenced protein synthesis, energy metabolism, cytoskeleton functions, immunity, and reproduction in both male and female mussels. Protein-protein interaction (PPI) networks indicated that protein synthesis and energy metabolism were the main biological processes influenced by TCPP. However, DEPs involved in these processes and their interaction patterns were quite different between male and female mussels. Basically, twelve ribosome DEPs which directly or indirectly interacted were found in protein synthesis in TCPP-exposed male mussels, while only 3 ribosome DEPs (not interacted) in TCPP-exposed female mussels. In energy metabolism, only 4 DEPs (with the relatively simple interaction pattern) mainly resided in fatty acid metabolism, butanoate/propanoate metabolism and glucose metabolism were discovered in TCPP-exposed male mussels, and more DEPs (with multiple interactions) functioned in TCA cycle and pyruvate/glyoxylate/dicarboxylate metabolism were found in TCCP-exposed female mussels. Taken together, TCPP induced gender-specific toxicological effects in mussels, which may shed new lights on further understanding the toxicological mechanisms of TCPP in aquatic organisms.

Dichlorvos is a common crop insecticide widely used by people which causes extensive and serious environmental pollution. However, it has been shown that organophosphorus poisoning causes energy metabolism and neural disorders. The overall purpose of this study was to investigate the damage to brain tissue and the changes in AMPK signaling pathway-related gene expression after dichlorvos poisoning in chickens. White-feathered broiler chickens, as the research subjects of this experiment, were divided into three groups: control group, low-dose group (77.5% dichlorvos at 1.13 mg/kg dose) and high-dose group (77.5% dichlorvos at 10.2 mg/kg dose). Clinical symptoms were observed after modeling, and an integrative analysis was conducted using HE staining microscopy, immune-histochemical microscopy, electron microscopy and PCR arrays. The results showed that the high-dose group had more obvious dyspnea, salivation, convulsion and other neurological phenomena. Pathological sections showed that nuclear disintegration of neurons was most obvious in the low-dose group, and apoptosis of brain cells was most obvious in the high-dose group, and the mitochondrial structure was destroyed in the two poisoned group, i.e. low-dose group and high-dose group. PCR arrays showed that AMPK signaling pathway was inhibited and the expressions of genes involved in energy metabolism (ACACA and PRKAA1) were significantly changed. Furthermore, genes associated with protein synthesis (EIF4EBP1) were significantly upregulated. FASN and HMGCR expressions were significantly increased. There were significant changes in the expressions of cell cycle-related genes (STK11, TP53 and FOXO3). Organophosphate poisoning can cause a lot of nuclear disintegration of brain neurons, increases cell apoptosis, disrupts the energy metabolism of mitochondrial structure, and inhibits the AMPK signaling pathway. These results provide a certain idea and basis for studying the mechanism of AMPK signaling after organophosphorus poisoning and provide a research basis for the prevention and treatment of organophosphorus poisoning.

Excess fluoride in drinking water is an environmental issue of increasing worldwide concern, because of its adverse effect on human health. Skeletal fluorosis caused by chronic exposure to excessive fluoride is a metabolic bone disease characterized by accelerated bone turnover accompanied by aberrant activation of osteoblasts. It is not clear whether Wnt/β-catenin signaling, an important signaling pathway regulating the function of osteoblasts, mediates the pathogenesis of skeletal fluorosis. A cross-sectional case-control study was conducted in Tongyu County, Jilin Province, China showed that fluoride stimulated the levels of OCN and OPG, resulting in accelerated bone turnover in patients with skeletal fluorosis. To investigate the influence of fluoride on Wnt/β-catenin signaling pathway, 64 male BALB/c mice were allotted randomly to four groups and treated with deionized water containing 0, 55, 110 and 221 mg/L NaF for 3 months, respectively. The results demonstrated that fluoride significantly increased mouse cancellous bone formation and the protein expression of Wnt3a, phospho-GSK3β (ser 9) and Runx2. Moreover, partial correlation analysis indicated that there was no significant correlation between fluoride exposure and Runx2 protein levels, after adjusting for β-catenin, suggesting that β-catenin might play a crucial role in fluoride-induced aberrant osteogenesis. In vivo, viability of SaoS2 cells was significantly facilitated by 4 mg/L NaF, and fluoride could induce the abnormal activation of Wnt/β-catenin signaling, the expression of its target gene Runx2 and significantly increased Tcf/Lef reporter activity. Importantly, inhibition of β-catenin suppressed fluoride-induced Runx2 protein expression and the osteogenic phenotypes. Taken together, the present study provided in vivo and in vitro evidence reveals a potential mechanism for fluoride-induced aberrant osteoblast activation and indicates that β-catenin is the pivot molecule mediating viability and differentiation of osteoblasts and might be a therapeutic target for skeletal fluorosis.