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.

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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 cm 3 ) and weight (0.637 ± 0.406 g) than the control group (0.067 ± 0.039 cm 3 ; 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.

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The occurrence of thyroid dysfunction is affected by environmental factors, and BPA is a ubiquitous environmental pollutant with the potential to cause thyroid dysfunction. However, the limited epidemiological evidence shows an inconsistent association between BPA exposure and thyroid dysfunction. Therefore, the literature on the impact of BPA on thyroid was sorted and analyzed to study the relationship between BPA and adult thyroid function. The studies published on or before 23rd May 2022 from PubMed, Web of Science, and Scopus were collected analyzing the association between BPA exposure and the levels of thyroid hormones. The methodological quality of each study was assessed, the sensitivity analysis and subgroup analysis based on study population and gender were also performed, and publication bias was evaluated. A total of 2969 literature studies were retrieved. Based on inclusion and exclusion criteria, eleven studies were included. Our results showed that BPA concentration was negatively correlated with FT4 and TSH in males. Pooled correlation coefficients between BPA and FT4/TSH were −0.027 (95%CI = −0.030∼−0.024) and −0.058 (95%CI = −0.111∼−0.004). BPA concentration was positively correlated with FT4 in females, and the pooled correlation coefficient was 0.006 (95%CI = 0.003–0.008). The effects of BPA on thyroid hormone levels were significantly different between males and females. BPA may significantly decrease the levels of FT4 and TSH in males but increase the levels of FT4 in females. Considering the high heterogeneity among studies and the limited investigations into subgroups, the relationship between BPA exposure and thyroid dysfunction needs to be further investigated.