Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants (POPs) that have adverse effects on human health. However, the long-term health effects and potential mechanism of neonatal exposure to PCBs are still unclear. In this study, nursing male mice exposed to PCB138 at 0.5, 5, and 50 μg/kg body weight (bw) from postnatal day (PND) 3 to PND 21 exhibited increased serum uric acid levels and liver uric acid synthase activity at 210 days of age. We also found an increased kidney somatic index in the 50 μg/kg group and kidney fibrosis in the 5 and 50 μg/kg groups. Mechanistically, PCB138 induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which might have led to inflammatory responses, such as activation of the NF-κB (nuclear factor kappa-B) and NLRP3 (NOD-like receptor protein 3) pathways. The inflammatory response might regulate renal fibrosis and hypertrophy. In summary, this study reports a long-term effect of neonatal PCB exposure on uric acid metabolism and secondary nephrotoxicity and clarifies the underlying mechanism. Our work also indicates that early life pollutant exposure may be an important cause of diseases later in life.

In recent years, the cardiovascular toxicity of urban fine particulate matter (PM₂.₅) has sparked significant alarm. Mitochondria produce 90% of ATP and make up 30% of the volume of cardiomyocytes. Thus knowledge of myocardial mitochondrial dysfunction due to PM₂.₅ exposure is essential for further cardiotoxic effects. Here, the mechanism of PM₂.₅-induced cardiac hypertrophy through calcium overload and mitochondrial dysfunction was investigated in vivo and in vitro. Male and female BALB/c mice were given 1.28, 5.5, and 11 mg PM₂.₅/kg bodyweight weekly through oropharyngeal inhalation for four weeks and were assigned to low, medium, and high dose groups, respectively. PM₂.₅-induced myocardial edema and cardiac hypertrophy were detected in the high-dose group. Mitochondria were scattered and ruptured with abnormal ultrastructural morphology. In vitro experiments on human cardiomyocyte AC16 showed that exposure to PM₂.₅ for 24 h caused opened mitochondrial permeability transition pore --leading to excessive calcium production, decreased mitochondrial membrane potential, weakened mitochondrial respiratory metabolism capacity, and decreased ATP production. Nevertheless, the administration of calcium chelator ameliorated the mitochondrial damage in the PM₂.₅-treated group. Our in vivo and in vitro results confirmed that calcium overload under PM₂.₅ exposure triggered mTOR/AKT/GSK-3β activation, leading to mitochondrial bioenergetics dysfunction and cardiac hypertrophy.

Di-(2-ethylhexyl) phthalate (DEHP) is a prevalent environmental contaminant that severely impacts the health of human and animals. Taxifolin (TAX), a plant flavonoid isolated from yew, exerts protective effects on cardiac diseases. Nevertheless, whether DEHP could induce cardiomyocyte hypertrophy and its mechanism remains unclear. This study aimed to highlight the specific molecular mechanisms of DEHP-induced cardiomyocyte hypertrophy and the protective potential of TAX against it. Chicken primary cardiomyocytes were treated with DEHP (500 μM) and/or TAX (0.5 μM) for 24 h. The levels of glucose and adenosine triphosphate (ATP) were detected, and cardiac hypertrophy-related genes were validated by real-time quantitative PCR (qRT-PCR) and Western blot (WB) in vitro. The results showed that DEHP-induced cardiac hypertrophy was ameliorated by TAX, as indicated by the increased cardiomyocyte area and expression of atrial natriuretic peptide (ANP), natriuretic peptides A-like (BNP) and β-myosin heavy cardiac muscle (β-MHC). Furthermore, DEHP induced cardiac hypertrophy via the interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in vitro. In addition, DEHP disrupted mitochondrial function and glycometabolism by activating the insulin-like growth factor 1 (IGF1)/phosphatidylinositol 3-kinase (PI3K) pathway and the peroxisome proliferator activated receptors (PPARs)/PPARG coactivator 1 alpha (PGC-1α) pathway to induce cardiac hypertrophy in vitro. Intriguingly, those DEHP-induced changes were obviously alleviated by TAX treatment. Taken together, cardiac hypertrophy was induced by DEHP via activating the IL-6/JAK/STAT3 signaling pathway, triggering glycometabolism disorder and mitochondrial dysfunction in vitro, can be ameliorated by TAX. Our findings may provide a feasible molecular mechanism for the treatment of cardiomyocyte hypertrophy induced by DEHP.

Benzotriazole (BT) and its associated derivatives are used ubiquitously in industrial processes, and can be detected in indoor temperature coolants and in chemicals designed to inhibit corrosion. This chemical has been widely detected in aquatic environments and shows some degree of environmental persistence. Evidence has shown that BT exposure can negatively affect endocrine systems and can result in neurotoxicity in fish. However, no study has examined whether this chemical exhibits hepatotoxicity in fish, and if so, what are the underlying mechanism associated with the damage. To address this knowledge gap, we measured the liver proteome of adult male Chinese rare minnow (Gobiocypris rarus) exposed to either 0.05, 0.5, or 5 mg/L BT for 28 days. Overall, 17 proteins were induced and 9 were reduced in abundance following BT treatment (ratio > 1.5, p < 0.05). Pathway analysis revealed that cellular processes affected by BT included xenobiotic clearance, oxidative stress response, apoptosis, and translation. Moreover, transcripts related to these toxic pathways were also significantly affected by BT. In addition, rare minnows exposed to BT showed signs of hypertrophy of hepatocytes, nuclei pyknosis, and higher levels of cellular vacuolization compared to the controls, thus these early proteomic responses in the liver may be related to pathology (i.e. adverse outcome pathway). Our data demonstrate that BT dysregulates molecular responses in the liver and tissue pathology indicative of damage. This study provides new insight into BT hepatotoxicity in Chinese rare minnow.

2,4-Dichloro-6-nitrophenol (DCNP) is an environmental transformation product of 2,4-dichlorophenol that has been identified as widespread in effluent wastewater, but little is known about its toxicity because this compound is not regulated. Therefore, to investigate the endocrine disruption potency of DCNP in Chinese rare minnows (Gobiocypris rarus), adult and juvenile fish were exposed to various concentrations of DCNP (2, 20, and 200 μg/L) for 28 d. After 28 d exposure, the plasma vitellogenin (VTG) levels were reduced in females while increased in males and juvenile fish considerably, as compared with the control. These results suggested that DCNP affects the HPG-axis in a sex-dependent way. Testosterone (T) levels in the plasma were significantly lower in adult and juvenile fish and were accompanied by an increased estradiol (E2)/T ratio. Histopathological observation revealed hypertrophy of the hepatocytes and nuclear pyknosis in the liver, the inhibition of spermatogenesis in the testes, and the degeneration of oocytes in the ovaries after DCNP exposure. The expression pattern of selected genes indicated that the nuclear receptor, steroidogenesis and gonadotropin regulation pathways were perturbed after DCNP exposure. Above all, our results demonstrated that DCNP clearly had anti-androgenic activity in both adult and juvenile fish and can therefore be considered as an endocrine-disrupting chemical.

Epidemiological studies have demonstrated a strong association of ambient fine particulate matter (PM₂.₅) exposure with the increasing mortality by ischemic heart disease (IHD), but the involved mechanisms remain poorly understood. Herein, we found that the chronic exposure of real ambient PM₂.₅ led to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein in the myocardium of mice, accompanied by obvious myocardial injury and hypertrophy. Further data from the hypoxia-ischemia cellular model indicated that PM₂.₅-induced HIF-1α accumulation was responsible for the promotion of myocardial hypoxia injury. Moreover, the declined ATP level due to the HIF-1α-mediated energy metabolism remodeling from β-oxidation to glycolysis had a critical role in the PM₂.₅-increased myocardial hypoxia injury. The in-depth analysis delineated that PM₂.₅ exposure decreased the binding of prolyl hydroxylase domain 2 (PHD2) and HIF-1α and subsequent ubiquitin protease levels, thereby leading to the accumulation of HIF-1α. Meanwhile, factor-inhibiting HIF1 (FIH1) expression was down-regulated by PM₂.₅, resulting in the enhanced translocation of HIF-1α to the nucleus. Overall, our study provides valuable insight into the regulatory role of oxygen sensor-mediated HIF-1α stabilization and translocation in PM-exacerbated myocardial hypoxia injury, we suggest this adds significantly to understanding the mechanisms of haze particles-caused burden of cardiovascular disease.

As ubiquitous, persistent organic pollutants, polycyclic aromatic hydrocarbons (PAHs) have adverse impacts on human health. Phenanthrene (Phe) is one of the most abundant PAHs in the environment. However, the long-term effects of exposure to environmental level of Phe on the kidneys and the potential mechanisms are unclear. T helper (Th) cells, a subtype of CD4⁺ T cells that play a central role in the renal immune microenvironment. In this study, male mice were chronically exposed to 5, 50, and 500 ng/kg bw Phe every other day for total 210 days. Those results indicated that environmental Phe exposure caused kidney hypertrophy, injury and fibrosis in the mice. Chronic, long-term environmental level of Phe exposure did not significantly alter the innate immune response but induced adaptive immune response changes (Th1/Th2 related cytokines release), causing a type 1 immune response in the 5 ng/kg bw Phe group and a type 2 immune response in the high dose groups (50 and 500 ng/kg bw). This study provides novel insights into the roles of adaptive immune response in long-term PAH exposure-induced chronic kidney injury and fibrosis, which is beneficial for further understanding the potential health hazards of PAHs and providing new avenues for immune intervention strategies to alleviate PAHs toxicity.

Aquatic ecosystem health is the main concern to increasing pesticides application to control agricultural pests as it is the ultimate receptor of such materials. This study evaluated the impact of new metal-insecticide, the [Mg(hesp)₂(phen)], referred as MgHP, on fish using physiological, genetic, biochemical, and morphological biomarkers. The fish, Prochilodus lineatus, was exposed to 0 (control), 1, 10, 100, 1000 μg L⁻¹ MgHP, for 24 and 96 h. MgHP was not lethal but caused genotoxicity, altered hematological variables and, the activity of antioxidant and biotransformation enzymes and histology of liver, depending on concentration and time exposure. Hematocrit and erythrocyte number (RBC) increased without change hemoglobin content resulting in changes in hematimetric indexes after 24 h; after 96 h, only RBC was changed. Erythrocyte nuclear abnormalities and crenate cells increased after 24 h but, not after 96 h. Erythrocytes and hepatocytes indicated instability in DNA integrity however, the absence of micronuclei suggested DNA damage repairment. After 24 h, the antioxidant defense system and the phase II biotransformation enzyme was responsiveness and catalase activity decreased at high MgHP concentrations; the antioxidant response was triggered after 96 h. Hepatocyte hypertrophy, intracellular cytoplasmic substances, cytoplasm degeneration, melanomacrophage and hyperemia increased in fish exposed from 10 μg L⁻¹ to higher MgHP concentrations; the organ alteration index increased as MgHP concentration increased showing dose-dependence. Most of hematological and genotoxic effects occurred after 24 h exposure evidencing potential recover capability of organism by activation of the antioxidant defense system and DNA repairment mechanisms. Nevertheless, the histopathological changes in the liver was maintained over time at high MgHP concentrations, a concentration usually no environmental relevant. In conclusion, this data reinforced the importance of continuing research on MgHP effects in other organisms considering the promising use of such compound to control the leaf-cutter ants and other insects.

Tributyltin (TBT), an organotin compound once widely used in agriculture and industry, has been reported to induce obesity and endocrine disruption. Gut microbiota has a strong connection with the host’s physiology. Nevertheless, the influences of TBT exposure on gut microbiota and whether TBT-influenced gut microbiota is related to TBT-induced toxicity remain unclear. To fill these gaps, ICR (CD-1) mice were respectively exposed to TBT at NOEL (L-TBT) and tenfold NOEL (H-TBT) daily by gavage for 8 weeks in the current study. The results showed that TBT exposure significantly increased body weight as well as epididymal fat, and led to adipocyte hypertrophy, dyslipidemia and impaired glucose and insulin homeostasis in mice. Additionally, TBT exposure significantly decreased the levels of T4, T3 and testosterone in serum. Also of note, TBT exposure changed gut microbiota composition mainly by decreasing Bacteroidetes and increasing Firmicutes proportions. To confirm the role of gut microbiota in TBT-induced overweight and hormonal disorders, fecal microbiota transplantation was performed and the mice receiving gut microbiota from H-TBT mice had similar phenotypes with their donor mice including significant body weight and epididymal fat gain, glucose and insulin dysbiosis and hormonal disorders. These results suggested that gut microbiome altered by TBT exposure was involved in the TBT-induced increased body weight, impaired glucose and insulin homeostasis and endocrine disruption in mice, providing significant evidence and a novel perspective for better understanding the mechanism by which TBT induces toxicity.

This research aimed to evaluate the ecological risk of xenobiotics associated with agricultural activities by determining metal contents and biomarker responses using tucunaré (Cichla sp.) as a bioindicator. The work was conducted in the southwest region of the state of Tocantins, in the cities of Lagoa da Confusão and Pium. Water samples and specimens of Cichla sp. were collected in the Javaés and Formoso Rivers at three collection points (A, B and C). The concentrations of Cd, Pb, Cu, Cr, Mn, Ni and Zn in water and fish were analyzed. In fish, genotoxic, biochemical (glucose serum levels, AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and histological (gills and liver) biomarkers were assessed. In the water, the Cr and Mn concentrations at the three collection points exceeded the values for Class 1 rivers. In the muscle, Cr was above the maximum limit allowed for human consumption at the three collection points, although the values at Points B and C were not significantly different from that at Point A (p > 0.05). At the three collection points, the micronucleus test revealed a low frequency of micronuclei. Significant hyperglycemia and a decrease in the AST activity of the fish collected at Point C was observed. In the gills, the most frequent alterations were at Stages I and II, which indicated mild to moderate damage, and epithelial detachment was the most frequent variation. In the liver tissue, the most frequently observed histological changes were at Stages I and II and included cytoplasmic vacuolization, nuclear hypertrophy, dilated sinusoids and bile stagnation. The integrated evaluation of these biomarkers indicated that fish collected from areas with intense agricultural activities presented adaptive responses that were likely caused by the availability and bioaccumulation of certain xenobiotics in the environment.