RESUMO
BACKGROUND: With rapid increase in the global use of various plastics, microplastics (MPs) and nanoplastics (NPs) pollution and their adverse health effects have attracted global attention. MPs have been detected out in human body and both MPs and NPs showed female reproductive toxicological effects in animal models. Miscarriage (abnormal early embryo loss), accounting for 15-25% pregnant women worldwide, greatly harms human reproduction. However, the adverse effects of NPs on miscarriage have never been explored. RESULTS: In this study, we identified that polystyrene (PS) plastics particles were present in women villous tissues. Their levels were higher in villous tissues of unexplained recurrent miscarriage (RM) patients vs. healthy control (HC) group. Furthermore, mouse assays further confirmed that exposure to polystyrene nanoplastics (PS-NPs, 50 nm in diameter, 50 or 100 mg/kg) indeed induced miscarriage. In mechanism, PS-NPs exposure (50, 100, 150, or 200 µg/mL) increased oxidative stress, decreased mitochondrial membrane potential, and increased apoptosis in human trophoblast cells by activating Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3 signaling through mitochondrial pathway. The alteration in this signaling was consistent in placental tissues of PS-NPs-exposed mouse model and in villous tissues of unexplained RM patients. Supplement with Bcl-2 could efficiently suppress apoptosis in PS-NPs-exposed trophoblast cells and reduce apoptosis and alleviate miscarriage in PS-NPs-exposed pregnant mouse model. CONCLUSIONS: Exposure to PS-NPs activated Bcl-2/Cleaved-caspase-2/Cleaved-caspase-3, leading to excessive apoptosis in human trophoblast cells and in mice placental tissues, further inducing miscarriage.
Assuntos
Aborto Espontâneo , Nanopartículas , Gravidez , Feminino , Humanos , Animais , Camundongos , Aborto Espontâneo/induzido quimicamente , Poliestirenos/toxicidade , Caspase 3 , Microplásticos , Plásticos , Caspase 2 , Placenta , Apoptose , Modelos Animais de Doenças , Proteínas Proto-Oncogênicas c-bcl-2 , Nanopartículas/toxicidadeRESUMO
Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc-HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc-HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc-HZ10 transcription. Meanwhile, lnc-HZ10 also increases AhR levels by suppressing its CUL4B-mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc-HZ10 (mainly 1-447 nt) interacts with γ-H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc-HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage.
Assuntos
Aborto Espontâneo , Reparo de DNA por Recombinação , Humanos , Feminino , Camundongos , Gravidez , Animais , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Aborto Espontâneo/genética , Placenta/metabolismo , Trofoblastos/metabolismo , Proteínas Culina/genéticaRESUMO
Dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) are two typical non-volatile disinfection by-products (DBPs) found in drinking water. Increasing evidence has demonstrated that they show reproductive toxicity. However, whether they might have endocrine disrupting properties remains largely unknown. To discover this, we treated male mice or pregnant mice with 0, 1-, 102-, 103-, 104-, or 5â¯×â¯104-fold maximal concentration level (MCL) of DCAA or TCAA in drinking water. In male mice, the levels of testosterone in serum and androgen receptor (AR) in testis were declined with ≥â¯103-fold MCL of DCAA (26.4â¯mg/kg/d) or TCAA (52.7â¯mg/kg/d). In pregnant mice, miscarriage rates were increased with ≥â¯104-fold MCL of DCAA (264â¯mg/kg/d) or ≥â¯103-fold MCL of TCAA. The levels of FSH in serum were increased and those of estradiol and progesterone were reduced with ≥â¯103-fold MCL of DCAA or TCAA. The protein levels of estrogen receptors (ERα and ERß) in ovary were reduced with ≥â¯102-fold MCL of DCAA (2.64â¯mg/kg/d) or TCAA (5.27â¯mg/kg/d). Exposure to some certain fold MCL of DCAA or TCAA also altered the protein levels of ERα and ERß in uterus and placenta. Exposure to 5â¯×â¯104-fold MCL of both DCAA and TCAA showed the combined effects. Therefore, both DCAA and TCAA could be considered as novel reproductive endocrine disrupting chemicals, which might be helpful for further assessment of the toxicological effects of DCAA and TCAA and the awareness of reproductive endocrine disrupting properties caused by DCAA and TCAA in drinking water.
Assuntos
Água Potável , Disruptores Endócrinos , Gravidez , Feminino , Masculino , Animais , Camundongos , Água Potável/química , Desinfecção , Ácido Dicloroacético/análise , Ácido Tricloroacético/toxicidade , Disruptores Endócrinos/toxicidade , Receptor alfa de Estrogênio , Receptor beta de EstrogênioRESUMO
In our previous study, it showed that P-3F, a podophyllotoxin derivative, causes the increased level of p53 expression by enhancing p53 stability, resulting from blockage of the Mdm2-p53 feedback loop via nucleolus-to-nucleoplasm translocation of Rps27a in human cervical cancer HeLa cell line. However, the mechanism of regulating Rps27a localization remains to be studied. In the current study, it has been demonstrated that the level of protein interacting with carboxyl terminus 1 (PICT1), originally identified as a tumor suppressor, was decreased in a concentration-dependent manner in response to P-3F, leading to inhibition of human cervical cancer cell lines proliferation. Also remarkably, reduction of serine phosphorylation of STMN1 at position 16 induced by P-3F was required in the downregulation of PICT1, in which p53 activity was likely to be directly involved. Note as well that, PICT1 also played an important role in p53 stability enhancement by inhibiting Mdm2-mediated p53 ubiquitination due to Rps27a translocation from the nucleolus to the nucleoplasm to interact with Mdm2 following treatment with P-3F. Collectively, these findings indicated that P-3F, a microtubule polymerization inhibitor, promotes the decreased level of PICT1 expression, which is critical for regulating the Rps27a-Mdm2-p53 pathway against cervical cancer.