Advances in polychlorinated biphenyls-induced female reproductive toxicity.

Polychlorinated biphenyls (PCBs) are a class of endocrine-disrupting chemicals (EDCs) widely present in the environment. PCBs have been of concern due to their anti/estrogen-like effects, which make them more toxic to the female reproductive system. However, there is still a lack of systematic reviews on the reproductive toxicity of PCBs in females, so the adverse effects and mechanisms of PCBs on the female reproductive system were summarized in this paper. Our findings showed that PCBs are positively associated with lower pregnancy rate, hormone disruption, miscarriage and various reproductive diseases in women. In animal experiments, PCBs can damage the structure and function of the ovaries, uterus and oviducts. Also, PCBs could produce epigenetic effects and be transferred to the offspring through the maternal placenta, causing development retardation, malformation and death of embryos, and damage to organs of multiple generations. Furthermore, the mechanisms of PCBs-induced female reproductive toxicity mainly include receptor-mediated hormone disorders, oxidative stress, apoptosis, autophagy, and epigenetic modifications. Finally, we also present some directions for future research on the reproductive toxicity of PCBs. This detailed information provided a valuable reference for fully understanding the reproductive toxicity of PCBs.

PI3K/AKT/mTOR pathway mediated-cell cycle dysregulation contribute to malignant proliferation of mouse spermatogonia induced by microcystin-leucine arginine.

Environmental cyanotoxin exposure may be a trigger of testicular cancer. Activation of PI3K/AKT/mTOR signaling pathway is the critical molecular event in testicular carcinogenesis. As a widespread cyanotoxin, microcystin-leucine arginine (MC-LR) is known to induce cell malignant transformation and tumorigenesis. However, the effects of MC-LR on the regulatory mechanism of PI3K/AKT/mTOR pathway in seminoma, the most common testicular tumor, are unknown. In this study, mouse spermatogonia cell line (GC-1) and nude mice were used to investigate the effects and mechanisms of MC-LR on the malignant transformation of spermatogonia by nude mouse tumorigenesis assay, cell migration invasion assay, western blot, and cell cycle assay, and so forth. The results showed that, after continuous exposure to environmentally relevant concentrations of MC-LR (20 nM) for 35 generations, the proliferation, migration, and invasion abilities of GC-1 cells were increased by 120%, 340%, and 370%, respectively. In nude mice, MC-LR-treated GC-1 cells formed tumors with significantly greater volume (0.998 ± 0.768 cm3 ) and weight (0.637 ± 0.406 g) than the control group (0.067 ± 0.039 cm3 ; 0.094 ± 0.087 g) (P < .05). Furthermore, PI3K inhibitor Wortmannin inhibited the PI3K/AKT/mTOR pathway and its downstream proteins (c-MYC, CDK4, CCND1, and MMP14) activated by MC-LR. Blocking PI3K alleviated MC-LR-induced cell cycle disorder and malignant proliferation, migration and invasive of GC-1 cells. Altogether, our findings suggest that MC-LR can induce malignant transformation of mouse spermatogonia, and the PI3K/AKT/mTOR pathway-mediated cell cycle dysregulation may be an important target for malignant proliferation. This study provides clues to further reveal the etiology and pathogenesis of seminoma.

Chronic Exposure to Environmentally Relevant Concentrations of Microcystin-Leucine Arginine Causes Lung Barrier Damage through PP2A Activity Inhibition and Claudin1 Ubiquitination.

Microcystin-leucine arginine (MC-LR), ubiquitous in water and food, is a threat to public health. In the present study, after C57BL/6J mice were fed with environmental concentrations of MC-LR (0, 1, 30, 60, 90, and 120 µg/L) for 6, 9, and 12 months, it was found that MC-LR could enter into mouse lung tissues and cause microstructural damage, as shown by western blotting and HE staining. Electron microscopy examination showed that MC-LR could damage the lung barrier by disruption of the tight junctions, which was confirmed by the decreased expression of tight junction markers, including Occludin, Claudin1, and ZO-1. In addition, MC-LR also increased the ubiquitination of Claudin1, indicating that MC-LR could disrupt tight junctions by promoting the degradation of Claudin1. Furthermore, MC-LR increased the levels of TNF-α and IL-6 in mouse lung tissues, leading to pneumonia. Importantly, pretreatment with PP2A activator D-erythro-sphingosine (DES) was found to significantly alleviate MC-LR-induced decrease of Occludin and Claudin1 by inhibiting the P-AKT/Snail pathway in vitro. Together, this study revealed that chronic exposure to MC-LR causes lung barrier damage, which involves PP2A activity inhibition and enhancement of Claudin1 ubiquitination. This study broadens the awareness of the toxic effects of MC-LR on the respiratory system, which has deep implications for public health.

MicroRNA-122 overexpression promotes apoptosis and tumor suppressor gene expression induced by microcystin-leucine arginine in mouse liver.

Microcystin-leucine arginine (MC-LR), an important hepatoxin, has the effect of promoting hepatocarcinogenesis. MicroRNA-122 (miR-122), an important tumor suppressor in liver, plays an important role in promoting cell apoptosis. Previous studies found that the expression of miR-122 was reduced after MC-LR exposure in liver. In this study, C57BL/6 mice were exposed to saline, negative control agomir, and MC-LR with or without miR-122 agomir transfection. The results indicated that MC-LR promoted the expressions of tumor suppressor genes and decreased the expressions of anti-apoptotic proteins B cell lymphoma-2 (Bcl-2) and Bcl-2-like 2 (Bcl-w), causing hepatocyte apoptosis. Under MC-LR exposure, miR-122 agomir transfection could further increase the expressions of tumor suppressor genes and the release of cytochrome-c (Cyt-c) and decrease the expressions of Bcl-2 and Bcl-w. In conclusion, miR-122 reduction can mitigate MC-LR-induced apoptosis to a certain extent, which in turn, it is likely to have contributed to MC-LR-induced hepatocarcinogenesis.

The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells.

Microcystin-LR (MC-LR) is an intracellular toxin with multi-organ toxicity and the testis is one of its important target organs. Although there is increasing research on MC-LR in male reproductive toxicity, the association between DNA damage and autophagy induced by MC-LR in male germ cells are still unclear. Therefore, it is important to explore the mechanism of MC-LR-induced DNA damage and the role of the activated ATM/p53 signaling pathway in testicular toxicity. The present study showed that MC-LR exposure significantly reduced gonadal index and induced pathological damage of the testes in mice. In addition, MC-LR increased the oxidative stress-related indicator hydroxyl radical, accompanied by increased levels of DNA damage-related indicators gamma-H2AX, 8-hydroxy-2'-deoxyguanosine, the olive tail moment (OTM) and DNA content of comet tail (TailDNA%) in trailing cells. Moreover, MC-LR activated the ATM/p53 pathway by enhancing the phosphorylation levels of ATM, CHK2 and p53 proteins, and then led to cell autophagy, ultimately triggering disrupted testicular cell arrangement, reduced sperm count and spermatogenic cell shedding. Importantly, after pretreatment with the antioxidant NAC, the expression levels of DNA damage-related indicators and the extent of damage in male germ cells were significantly reduced. Furthermore, pretreatment with the ATM inhibitor KU55933 could reduce the occurrence of autophagy and mitigate testicular toxicity of MC-LR through inhibiting the activation of the ATM/p53 pathway. These results indicate that MC-LR-induced oxidative stress can activate the DNA damage-mediated ATM/p53 signalling pathway to induce autophagy in male germ cells. This study provides a novel insight to further clarify the reproductive toxicity caused by MC-LR and to protect male reproductive health.

Update on the adverse effects of microcystins on the liver.

Microcystins (MCs) are the most common cyanobacteria toxins in eutrophic water, which have strong hepatotoxicity. In the past decade, epidemiological and toxicological studies on liver damage caused by MCs have proliferated, and new mechanisms of hepatotoxicity induced by MCs have also been discovered and confirmed. However, there has not been a comprehensive and systematic review of these new findings. Therefore, this paper summarizes the latest advances in studies on the hepatotoxicity of MCs to reveal the effects and mechanisms of hepatotoxicity induced by MCs. Current epidemiological studies have confirmed that symptoms or signs of liver damage appear after human exposure to MCs, and a long time of exposure can even lead to liver cancer. Toxicological studies have shown that MCs can affect the expression of oncogenes by activating cell proliferation pathways such as MAPK and Akt, thereby promoting the occurrence and development of cancer. The latest evidence shows that epigenetic modifications may play an important role in MCs-induced liver cancer. MCs can cause damage to the liver by inducing hepatocyte death, mainly manifested as apoptosis and necrosis. The imbalance of liver metabolic homeostasis may be involved in hepatotoxicity induced by MCs. In addition, the combined toxicity of MCs and other toxins are also discussed in this article. This detailed information will be a valuable reference for further exploring of MCs-induced hepatotoxicity.

Role of microRNA-122 in microcystin-leucine arginine-induced dysregulation of hepatic iron homeostasis in mice.

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA-122 (miR-122) is specifically expressed in the liver. This study focuses on the role of miR-122 in MC-LR-induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 µg/kg·BW MC-LR, 25 µg/kg·BW MC-LR, Negative control agomir and 25 µg/kg·BW MC-LR + miR-122 agomir). The results show that MC-LR decreases the expressions of miR-122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR-122 agomir pretreatment improves MC-LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR-122 agomir can prevent the accumulation of hepatic iron induced by MC-LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL-6/STAT signaling pathways.

Epigenetic modification of H3K4 and oxidative stress are involved in MC-LR-induced apoptosis in testicular cells of SD rats.

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide, produced by aquatic cyanobacteria such as microcystis, with strong reproductive toxicity which poses greater threat to the reproductive abilities of humans and animals. By exploring the role of trimethylation of histone H3 at lysine 4 (H3K4me3) and the role of oxidative stress in MC-LR-induced apoptosis in testicular Sertoli cells in Sprague-Dawley (SD) rats, this study indicated that MC-LR increased the expression levels of apoptosis-related genes by raising the levels of H3K4me3. 5'-Deoxy-5'-methylthioadenosine (MTA), the inhibitor of H3K4me3, reduced apoptosis, indicating for the first time that epigenetic modification is closely related to the testicular reproductive toxicity induced by MC-LR. MC-LR also induced oxidative stress by stimulating the generation of reactive oxygen species (ROS), and subsequently triggering mitochondria-mediated apoptotic pathway by decreasing mitochondrial membrane potential and increasing the levels of Bax, Bcl-2, Caspase-3, and so on. MC-LR-induced apoptosis of testicular cells could be decreased after pretreatment with oxidative stress inhibitor N-acetyl-cysteine (NAC). Furthermore, the pathological damage to mitochondria and testes were observed in SD rats. These results show that MC-LR can induce apoptosis by raising the levels of H3K4me3, and pretreatment with MTA can ameliorate the MC-LR-induced apoptosis of cocultured cells by lowering the levels of H3K4me3. Furthermore, NAC has a protective effect on MC-LR-induced apoptosis of testicular cells in SD rats by inhibiting the oxidative stress.

The adverse health effects of bisphenol A and related toxicity mechanisms.

Bisphenol A (BPA) is an industrial component commonly used in synthesis of polycarbonate plastics, epoxy resin and other polymer materials. Due to its mass productions and widespread applications, the presence of BPA is ubiquitous in the environment. BPA can enter the body via different ways such as digestive tract, respiratory tract and dermal tract. As an endocrine disruptor, BPA has estrogen-like and anti-androgen effects causing damages to different tissues and organs, including reproductive system, immune system and neuroendocrine system, etc. Recently, it has been shown that BPA could induce carcinogenesis and mutagenesis in animal models. Here, the underlying mechanisms of BPA-induced multi-organ toxicity were well summarized, involving the receptor pathways, disruption of neuroendocrine system, inhibition of enzymes, modulation of immune and inflammatory responses, as well as genotoxic and epigenetic mechanisms. The aim of this review is to compile the available current research data regarding BPA and provide an overview of the current status of BPA exposure and relevant health effects covering reproductive, developmental, metabolic, immuno, respiratory, hepatic and renal toxicity and carcinogenesis of BPA. This review provides comprehensive data of BPA toxicity on human health and related mechanisms. We also identify any missing data which should be addressed by further studies.