Per- and polyfluoroalkyl substances (PFAS) have attracted significant attention due to their environmental toxicity. However, the detrimental impact of PFAS on the development of the female reproductive system remains controversial. In this study, we investigated the effects of three specific PFAS compounds perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) on ovarian development. Among these compounds, PFDA demonstrated the most pronounced cytotoxic effect on ovarian granulosa cells. The results showed that a 200 μM concentration of PFDA induced cell apoptosis via the intrinsic pathway by elevating reactive oxygen species (ROS) levels and activating Caspase-9 and Caspase-3. Furthermore, 200 μM PFDA triggered necroptosis, a form of regulated cell death (RCD), through the receptor-interacting serine/threonine kinase 1 (RIPK1), receptor interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like protein (MLKL) axis, mediated by inhibition of the canonical apoptosis proteolytic enzyme Caspase-8. In vivo experiments confirmed that mice exposed to PFDA displayed a significantly reduced ovarian index compared to the control group, accompanied by evident follicular atresia. Ovarian tissues from the PFDA-exposed group showed upregulated necroptosis markers, which were effectively mitigated by inhibiting the phosphorylation of RIPK1 at Ser166. Importantly, this study provides the first evidence that PFDA disrupts ovarian development through a novel mechanism involving the RIPK1-mediated necroptosis pathway, alongside the detection of the intrinsic apoptosis pathway. This greatly expands our insight into the effects of PFDA on cell death. This finding highlights the potential public health hazards associated with PFDA exposure and emphasizes the need for further research to fully understand its broader implications.
Per- and polyfluoroalkyl substances (PFAS), the versatile anthropogenic chemicals, are popular with the markets and manufactured in large quantities yearly. Accumulation of PFAS has various adverse health effects on human. Albeit certain members of PFAS were found to have genotoxicity in previous studies, the mechanisms underlying their effects on DNA damage repair remain unclear. Here, we investigated the effects of Perfluorodecanoic acid (PFDA) on DNA damage and DNA damage repair in ovarian epithelial cells through a series of in vivo and in vitro experiments. At environmentally relevant concentration, we firstly found that PFDA can cause DNA damage in primary mouse ovarian epithelial cells and IOSE-80 cells. Moreover, nuclear cGAS increased in PFDA-treated cells, which leaded to the efficiency of DNA homologous recombination (HR) decreased and DNA double-strand breaks perpetuated. In vivo experiments also verified that PFDA can induce more DNA double-strand breaks lesions and nuclear cGAS in ovarian tissue. Taken together, our results unveiled that low dose PFDA can cause deleterious effects on DNA and DNA damage repair (DDR) in ovarian epithelial cells and induce genomic instability.
Abstract Background It is well-known that long non-coding RNAs (lncRNAs) play essential roles in cancer development and progression. This study aimed to assess the potential prognostic value of specific lncRNAs in breast and gynecologic cancers. Methods PubMed, EMBASE, Cochrane library and TCGA databases were systematically searched from inception to January, 2019, and identified according to eligibility criteria. A random-effects model was adopted to calculate combined hazard ratios to explore the association between specific lncRNA expression level and survival in breast and gynecologic cancers. Subgroup and publication bias analyses were also conducted. Results 111 studies encompassing nearly 20000 participants and 25 lncRNAs were included in the current study. Of the listed lncRNAs, we identified 3 lncRNAs significantly associated with both overall survival (OS) and disease-free survival (DFS) in breast and gynecologic cancers, indicating that they might act as promising prognostic biomarkers in clinical applications. Specifically, HOTAIR and PVT1 had a negative impact on survival outcome, while GAS5 was associated with better prognosis. Further subgroup analyses identified HOTAIR as a biomarker for the poor survival whether in an Asian population or in European and American populations and GAS5 as a biomarker for the relatively good prognosis of both breast and gynecologic cancers. Conclusions We here highlight that abnormal expression of 3 lncRNAs, including HOTAIR, GAS5, PVT1 might significantly affect the survival of breast and gynecologic cancer patients and serve as novel prognostic biomarkers for breast and gynecologic cancers.
The mammalian Atg18 ortholog WIPI2 is a key regulator of LC3 lipidation to promote autophagosome biogenesis during nonselective macroautophagy, while its functions in selective autophagy such as mitophagy remain largely unexplored. In this study, we explored the role of WIPI2 in PINK1-PRKN/parkin-mediated mitophagy. First, we found that WIPI2 is recruited to damaged mitochondria upon mitophagy induction. Second, loss of WIPI2 impedes mitochondrial damaging agents-induced mitophagy. Third, at molecular level, WIPI2 binds to and promotes AAA-ATPase VCP/p97 (valosin containing protein) to damaged mitochondria; and WIPI2 depletion blunts the recruitment of VCP to damaged mitochondria, leading to reduction in degradation of outer mitochondrial membrane (OMM) proteins and mitophagy. Finally, WIPI2 is implicated in cell fate decision as cells deficient in WIPI2 are largely resistant to cell death induced by mitochondrial damage. In summary, our study reveals a critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote OMM protein degradation and eventual mitophagy.Abbreviations: ATG, autophagy related; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide chlorophenylhydrazone; CYCS, cytochrome c, somatic; HSPD1/HSP60, heat shock protein family D (Hsp60) member 1; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; NPLOC4, NPL4 homolog, ubiquitin recognition factor; OMM, outer mitochondrial membrane; OPTN, optineurin; PtdIns3P, phosphatidylinositol-3-phosphate; PINK1, PTEN induced kinase 1; PRKN/Parkin, parkin RBR E3 ubiquitin protein ligase; UBXN6/UBXD1, UBX domain protein 6; UFD1, ubiquitin recognition factor in ER associated degradation 1; VCP/p97, valosin containing protein; WIPI2, WD repeat domain, phosphoinositide interacting 2
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