Perfluoroalkyl Substance Exposure and the BDNF Pathway in the Placental Trophoblast.

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in humans and the environment. In utero PFAS exposure is associated with neurodevelopmental effects; however, the mechanism is poorly understood. Brain-derived neurotrophic factor (BDNF) signaling is critical to fetal neurodevelopment during pregnancy and maintains important regulatory roles later in life. This study aims to characterize placental BDNF signaling and investigate whether PFAS exposure disrupts the signaling pathway in placental trophoblast cells. Methods: The expression and localization of BDNF receptors-p75NTR and TrkB-in first trimester and term human placentas and trophoblast cells were investigated by immunofluorescence staining. To assess the effects of PFAS exposure on the BDNF pathway, BeWo cells were treated with PFAS mixtures that mimicked blood levels in a highly exposed population and major PFAS compounds in the mixture at 0.01, 0.1, 1, and 10 µM concentrations. Changes in pro-BDNF levels and phosphorylation of TrkB receptors were examined by Western blot. Results: In first trimester human placentas, TrkB and p75NTR receptors were primarily localized to syncytiotrophoblast and cytotrophoblast cells. At term, TrkB and p75NTR receptors were primarily observed in the placental villous stroma. TrkB receptor staining in trophoblasts was reduced at term, while p75NTR receptor staining was negative. TrkB receptors were confined to the nuclear and perinuclear spaces, and phosphorylation occurred at the Tyr816 residue in BeWo cells. Exposure to PFOS, PFOA, PFBS, and the six-PFAS mixture did not significantly affect BDNF levels or activation (phosphorylation) of TrkB. Treating cells with 1 µM and 10 µM of PFNA resulted in increased TrkB phosphorylation compared to unexposed controls, but BDNF levels were unchanged. Conclusions: BDNF receptors are present in different regions of human placental villi, indicating diverse functions of BDNF signaling in placental development. Our findings suggest that the BDNF pathway in placental trophoblast cells is not disrupted by exposures to PFOS, PFOA, PFBS, and a PFAS mixture, but may be affected by PFNA exposures. Further investigation is needed on how PFAS affects other critical signaling pathways during fetal neurodevelopment.

Learning to learn by yourself: Unsupervised meta-learning with self-knowledge distillation for COVID-19 diagnosis from pneumonia cases.

The goal of diagnosing the coronavirus disease 2019 (COVID-19) from suspected pneumonia cases, that is, recognizing COVID-19 from chest X-ray or computed tomography (CT) images, is to improve diagnostic accuracy, leading to faster intervention. The most important and challenging problem here is to design an effective and robust diagnosis model. To this end, there are three challenges to overcome: (1) The lack of training samples limits the success of existing deep-learning-based methods. (2) Many public COVID-19 data sets contain only a few images without fine-grained labels. (3) Due to the explosive growth of suspected cases, it is urgent and important to diagnose not only COVID-19 cases but also the cases of other types of pneumonia that are similar to the symptoms of COVID-19. To address these issues, we propose a novel framework called Unsupervised Meta-Learning with Self-Knowledge Distillation to address the problem of differentiating COVID-19 from pneumonia cases. During training, our model cannot use any true labels and aims to gain the ability of learning to learn by itself. In particular, we first present a deep diagnosis model based on a relation network to capture and memorize the relation among different images. Second, to enhance the performance of our model, we design a self-knowledge distillation mechanism that distills knowledge within our model itself. Our network is divided into several parts, and the knowledge in the deeper parts is squeezed into the shallow ones. The final results are derived from our model by learning to compare the features of images. Experimental results demonstrate that our approach achieves significantly higher performance than other state-of-the-art methods. Moreover, we construct a new COVID-19 pneumonia data set based on text mining, consisting of 2696 COVID-19 images (347 X-ray + 2349 CT), 10,155 images (9661 X-ray + 494 CT) about other types of pneumonia, and the fine-grained labels of all. Our data set considers not only a bacterial infection or viral infection which causes pneumonia but also a viral infection derived from the influenza virus or coronavirus.

Perfluorobutane sulfonate exposure disrupted human placental cytotrophoblast cell proliferation and invasion involving in dysregulating preeclampsia related genes.

We reported that maternal PFBS, an emerging pollutant, exposure is positively associated with preeclampsia which can result from aberrant trophoblasts invasion and subsequent placental ischemia. In this study, we investigated the effects of PFBS on trophoblasts proliferation/invasion and signaling pathways. We exposed a human trophoblast line, HTR8/SVneo, to PFBS. Cell viability, proliferation, and cell cycle were evaluated by the MTS assay, Ki-67 staining, and flow cytometry, respectively. We assessed cell migration and invasion with live-cell imaging-based migration assay and matrigel invasion assay, respectively. Signaling pathways were examined by Western blot, RNA-seq, and qPCR. PFBS exposure interrupted cell proliferation and invasion in a dose-dependent manner. PFBS (100 µM) did not cause cell death but instead significant cell proliferation without cell cycle disruption. PFBS (10 and 100 µM) decreased cell migration and invasion, while PFBS (0.1 µM) significantly increased cell invasion but not migration. Further, RNA-seq analysis identified dysregulated HIF-1α target genes that are relevant to cell proliferation/invasion and preeclampsia, while Western Blot data showed the activation of HIF-1α, but not Notch, ERK1/2, (PI3K)AKT, and P38 pathways. PBFS exposure altered trophoblast cell proliferation/invasion which might be mediated by preeclampsia-related genes, suggesting a possible association between prenatal PFBS exposure and adverse placentation.

Maternal serum concentrations of perfluoroalkyl acids in five international birth cohorts.

BACKGROUND: Perfluoroalkyl acids (PFAAs) are persistent and bioaccumulating compounds, which are spread all over the globe. We aimed to compare the PFAA concentrations in serum from pregnant women in five birth cohorts from four countries (Denmark, China, Norway, and Greenland). METHODS: Serum samples were obtained from the following five birth cohorts including a total of 4718 pregnant women: the Danish National Birth Cohort (DNBC, years 1996-2002, Denmark), the Aarhus Birth Cohort (ABC, years 2008-2013, Denmark), the Shanghai Birth Cohort (SBC, years 2013-2015, China), the Northern Norway Mother-Child Contaminant Cohort (MISA, years 2007-2009, Norway), and the Greenlandic Birth Cohort (ACCEPT, years 2010-2013, Greenland). The samples were analyzed using liquid chromatography triple-quadrupole mass spectrometry. To ensure comparability, all samples except for the MISA samples were measured in the same laboratory. We adjusted the log-transformed PFAA concentrations for age and parity using analysis of covariance. RESULTS AND DISCUSSION: The geometric mean (GM) of the summed concentrations of the seven most abundant PFAAs (∑PFAA) was 35ng/mL in the DNBC, 25 ng/mL in the SBC, 18ng/mL in the ACCEPT, 12ng/mL in the MISA cohort, and 12ng/mL in the ABC. The DNBC concentration was highest presumably because these samples were taken in earlier years (i.e. 1996-2002) than the samples from the other cohorts (i.e. 2007-2015), and at a time when the production of PFAAs were at the highest. When excluding the DNBC samples, we found that the concentrations of all the perfluorinated sulfonic acids (PFSAs) and one of the four perfluorinated carboxylic acids (PFCAs) were highest in the Greenlandic women, whereas the other three PFCAs were highest in the Chinese women. CONCLUSION: The concentration and composition of serum PFAAs were similar for the Danish ABC women and the Norwegian MISA women but were otherwise different across the cohorts. The different exposure profiles might partly be related to differences in lifestyle and diet. As the concentrations and compositional patterns vary between the countries, we suggest that the health implications associated with high PFAA exposure might also differ between the countries.