The association between polycyclic aromatic hydrocarbons (PAHs) and male reproductive dysfunction has attracted increasing attention. The purpose of this study was to compare the male reproductive toxicity of multiple PAHs and to investigate the underlying molecular mechanisms. TM4 cells (mouse testicular Sertoli cells, SCs) were treated with benzo(a)pyrene (BaP), pyrene (Py), fluoranthene (Fl) and phenanthrene (Phe) (0, 0.1, 1, 10, 50, or 100 μM) for varying time points (4, 12, 24, or 48 h), and male C57BL/6 mice were administered BaP and Py (0, 10, 50, or 100 mg/kg body weight) for 14 days based on the cell experimental results. Histopathological examination, western blotting, ELISA, biochemical assays, RT–PCR, flow cytometry, JC-1 staining and trans-epithelium electrical resistance (TEER) measurements were used to assess apoptosis, blood-testis barrier (BTB) integrity, intracellular calcium ([Ca²⁺]ᵢ) concentrations and oxidative stress (OS). The results revealed that the mRNA levels and enzymatic activities of CYP450 and GST family members; levels of ROS, MDA, cleaved caspase 3 (c-caspase 3), caspase 9, Bax, and cytochrome C (CytC); and numbers of TUNEL-positive cells were significantly increased by BaP and Py, while levels of AhR, GSH, SOD, CAT, Bcl-2 and ΔΨm were decreased. Additionally, BaP and Py notably interfered with tight junctions (TJs) and adherens junctions (AJs) in the BTB. Intriguingly, BaP, but not Py, induced [Ca²⁺]ᵢ overload and gap junction (GJ) destruction. There was no dramatic effect of Fl and/or Phe on any of the above parameters except that slight cytotoxicity was observed with higher doses of Fl. Collectively, these findings showed that BaP and Py elicited SC apoptosis and BTB disruption involving mitochondrial dysfunction and OS, but [Ca²⁺]ᵢ fluctuation and GJ injury were only observed with BaP-induced reproductive toxicity. The male reproductive toxicity of the selected PAHs was ranked in the order of BaP > Py > Fl > Phe.

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.

The use of biomass for cooking and heating is considered an important factor associated with chronic obstructive pulmonary disease (COPD), but few studies have previously addressed its underlying mechanisms. Therefore, this research aimed to evaluate the effects of biomass-related PM₂.₅ (BRPM₂.₅) exposure on 16HBE human airway epithelial cells and in mice with regard to mitochondrial dysfunction. Our study indicated that BRPM₂.₅ exposure of 16HBE cells resulted in mitochondrial dysfunction, including decreased mitochondrial membrane potential, increased expression of fission proteins-phospho-DRP1, increased mitochondrial ROS (mtROS), and decreased levels of ATP. BRPM₂.₅ altered the mitochondrial metabolism of 16HBE cells by decreasing mitochondrial oxygen consumption and glycolysis. However, Mitochondria targeted peptide SS-31 eliminated mitochondrial ROS and alleviated the ATP deficiency and proinflammatory cytokines release. BRPM2.5 exposure resulted in abnormal mitochondrial morphological alterations both in 16HBE and in lung tissue. Taken together, these results suggest that BRPM₂.₅ has detrimental effects on human airway epithelial cells, leading to mitochondrial dysfunction, abnormal mitochondrial metabolism and altered mitochondrial dynamics. The present study provides the first evidence that disruption of mitochondrial structure and mitochondrial metabolism may be one of the mechanisms of BRPM₂.₅-induced respiratory dysfunction.

Embryonic exposure to environmental chemicals may result in specific chronic diseases in adulthood. Parabens, a type of environmental endocrine disruptors widely used in pharmaceuticals and cosmetics, have been shown to cause a decline in women's reproductive function. However, whether exposure to parabens during pregnancy also negatively affect the ovarian function of the female offspring in adulthood remains unclear. This study aims to investigate the effects of prenatal propylparaben (PrP) exposure on the ovarian function of adult mice aged 46 weeks, which is equivalent to the age of 40 years in women. Pregnant ICR mice were intraperitoneally injected with human-relevant doses of PrP (i.e., 0, 7.5, 90, and 450 mg/kg/day) during the fetal sex determination period—from embryonic day E7.5 to E13.5. Our results revealed that ovarian aging was accelerated in PrP-exposed mice at 46 weeks, with altered regularity of the estrous cycle, decreased serum estrogen (E2) and progesterone (P4) levels, reduced size of the primordial follicle pool, and increased number of atretic follicles. It was found that prenatal exposure to human-relevant doses of PrP exacerbated ovarian oxidative stress, inflammation, and fibrosis, which promoted follicular atresia by activating the mitochondrial apoptosis pathway. To compensate, the depletion of primordial follicles was also accelerated by activating the PI3K/AKT/mTOR signaling pathway in PrP-exposed mice. Moreover, PrP induced hypermethylation of CpG sites in the promoter region of Cyp11a1 (a 17.16–64.28% increase) partly led to the disrupted steroidogenesis, and the altered methylation levels of imprinted genes H19 and Peg3 may also contribute to the phenotypes observed. These remarkable findings highlight the embryonic origin of ovarian aging and suggest that a reduced use of PrP during pregnancy should be advocated.

The Pearl River Estuary (PRE) is the largest estuary in southern China and under high metal stress. In the present study, we employed an integrated method of transcriptomics and proteomics to investigate the ecotoxicological effects of trace metals on the Hong Kong oyster Crassostrea hongkongensis. Three oyster populations with distinct spatial distributions of metals were sampled, including the Control (Station QA, the lowest metal levels), the High Cd (Station JZ, the highest Cd), and the High Zn–Cu–Cr–Ni (Station LFS, with the highest levels of zinc, copper, chromium, and nickel). Dominant metals in oysters were differentiated by principal component analysis (PCA), and theirgene and protein profiles were studied using RNA-seq and iTRAQ techniques. Of the 2250 proteins identified at both protein and RNA levels, 70 proteins exhibited differential expressions in response to metal stress in oysters from the two contaminated stations. There were 8 proteins altered at both stations, with the potential effects on mitochondria and endoplasmic reticulum by Ag. The genotoxicity, including impaired DNA replication and transcription, was specifically observed in the High Cd oysters with the dominating influence of Cd. The structural components (cytoskeleton and chromosome-associated proteins) were impaired by the over-accumulated Cu, Zn, Cr, and Ni at Station LFS. However, enhanced tRNA biogenesis and exosome activity might help the oysters to alleviate the toxicities resulting from their exposure to these metals. Our study provided comprehensive information on the molecular changes in oysters at both protein and RNA levels in responding to multi-levels of trace metal stress.

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.

The surface modifications of nanoparticles (NPs), are well-recognized parameters that affect the toxicity, while there has no study on toxicity of Al₂O₃ NPs with different surface modification. Therefore, for the first time, this study pays attention to evaluating the toxicity and potential mechanism of pristine Al₂O₃ NPs (p-Al₂O₃), hydrophilic (w-Al₂O₃) and lipophilic (o-Al₂O₃) modifications of Al₂O₃ NPs both in vitro and in vivo. Applied concentrations of 10, 20, 40, 80,100 and 200 μg/mL for 24 h exposure on Caenorhabditis elegans (C. elegans), while 100 μg/mL of Al₂O₃ NPs significantly decreased the survival rate. Using multiple toxicological endpoints, we found that o-Al₂O₃ NPs (100 μg/mL) could induce more severe toxicity than p-Al₂O₃ and w-Al₂O₃ NPs. After uptake by C. elegans, o-Al₂O₃ NPs increased the intestinal permeability, easily swallow and further destroy the intestinal membrane cells. Besides, cytotoxicity evaluation revealed that o-Al₂O₃ NPs (100 μg/mL) are more toxic than p-Al₂O₃ and w-Al₂O₃. Once inside the cell, o-Al₂O₃ NPs could attack mitochondria and induce the over-production of reactive oxygen species (ROS), which destroy the intracellular redox balance and lead to apoptosis. Furthermore, the transcriptome sequencing and RT-qPCR data also demonstrated that the toxicity of o-Al₂O₃ NPs is highly related to the damage of cell membrane and the imbalance of intracellular redox. Generally, our study has offered a comprehensive sight to the adverse effects of different surface modifications of Al₂O₃ NPs on environmental organisms and the possible underlying mechanisms.

The hazardous effects of herbicides are well known; however, their effects on the reproductive system remain unclear. In this study, we demonstrated the anti-proliferative effects of dinitramine (DN) on immature murine testicular cell lines (Leydig and Sertoli cells) mediated via endoplasmic reticulum (ER) stress-induced calcium dysregulation in the cytosol and mitochondria. The results demonstrated that the viability and proliferation of DN-treated TM3 and TM4 cells decreased significantly, even in the spheroid state. DN induced the apoptosis of TM3 and TM4 cells and decreased the expression of genes related to cell cycle progression. Treatment with DN increased the cytosolic and intramitochondrial levels of calcium by activating ER stress signals. DN activated the Erk/P38/Jnk Mapk pathway and inactivated the Pi3k/Akt pathway in murine testicular cells. Co-treatment with 2-aminoethoxydiphenyl borate (2-APB) mitigated DN-induced calcium upregulation in both testicular cell lines. Although 2-APB did not antagonize the anti-proliferative effect of DN in TM3 cells, treatment with 2-APB and 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid restored the proliferation of DN-treated TM4 cells.

Cetaceans accumulate persistent and toxic substances such as polybrominated diphenyl ethers in their tissue. PBDEs are ubiquitous in marine environments, and their exposure to mammals is linked to numerous health effects such as endocrine disruption, neurotoxicity, carcinogenicity, and fetal toxicity. However, the toxicological effects and mechanism of toxicity in cetaceans remains poorly understood. The effects of BDE-47 (0.1–0.5 μg mL⁻¹), BDE-100 (0.1–0.5 μg mL⁻¹), and BDE-209 (0.25–1.0 μg mL⁻¹) exposure on cell viability, oxidative stress, mitochondrial structure, and apoptosis were evaluated using a recently established pantropical spotted dolphin (Stenella attenuata) skin fibroblast cell line (PSD-LWHT) as an in vitro model. However, the production of reactive oxygen species (ROS) increased following exposure to 1.0 μg mL⁻¹ PBDE while superoxide anion, hydroxyl radicals, and inducible nitric oxide increased in a dose-dependent manner. At 0.5–1.0 μg mL⁻¹, PBDEs significantly reduced the mitochondrial membrane potential. In addition, exposure to BDE-47 and -209 significantly affected mitochondrial structure as well as cell signaling and transduction compared to BDE-100. Although PBDE exposure did not affect cell viability, a significant increase in cell apoptosis markers (Bcl2 and caspase-9) was observed. This study demonstrated that BDE-47, -100, and −209 congeners might cause cytotoxic and genotoxic effects as they play a crucial role in the dysregulation of oxidative stress and alteration of mitochondrial and cell membrane structure and activity in the fibroblast cells. Hence, these results suggest that PBDEs might have adverse health effects on cetaceans inhabiting contaminated marine environments.

Fipronil, a phenyl-pyrazole insecticide, has a wide range of uses, from agriculture to veterinary medicine. Due to its large-scale applications, the risk of environmental and occupational exposure and bioaccumulation raises concerns. Moreover, relatively little is known about the intracellular mechanisms of fipronil in trophoblasts and the endometrium involved in implantation. Here, we demonstrated that fipronil reduced the viability of porcine trophectoderm and luminal epithelial cells. Fipronil induced cell cycle arrest at the sub-G1 phase and apoptotic cell death through DNA fragmentation and inhibition of DNA replication. These reactions were accompanied by homeostatic changes, including mitochondrial depolarization and cytosolic calcium depletion. In addition, we found that exposure to fipronil compromised the migration and implantation ability of pTr and pLE cells. Moreover, alterations in PI3K-AKT and MAPK-ERK1/2 signal transduction were observed in fipronil-treated pTr and pLE cells. Finally, the antiproliferative and apoptotic effects of fipronil were also demonstrated in 3D cell culture conditions. In summary, our results suggest that fipronil impairs implantation potentials in fetal trophectoderm and maternal endometrial cells during early pregnancy.