Department of Obstetrics and Gynecology, Duke University, Durham, NC, United States.
Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Public Health, Shanghai Jiao-Tong University School of Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2021 Jul 28;12:694885. doi: 10.3389/fendo.2021.694885. eCollection 2021.
Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in humans and the environment. 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.
The expression and localization of BDNF receptors-p75 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.
In first trimester human placentas, TrkB and p75 receptors were primarily localized to syncytiotrophoblast and cytotrophoblast cells. At term, TrkB and p75 receptors were primarily observed in the placental villous stroma. TrkB receptor staining in trophoblasts was reduced at term, while p75 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.
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.
全氟和多氟烷基物质（PFAS）是持久性有机污染物，在全球范围内的人类和环境中无处不在。PFAS 暴露与神经发育效应有关；然而，其机制尚不清楚。脑源性神经营养因子（BDNF）信号对于妊娠期间胎儿的神经发育至关重要，并在生命后期维持着重要的调节作用。本研究旨在描述胎盘 BDNF 信号，并研究 PFAS 暴露是否会破坏胎盘滋养细胞中的信号通路。
通过免疫荧光染色研究了 BDNF 受体-p75 和 TrkB 在人胎盘和滋养细胞中的表达和定位。为了评估 PFAS 暴露对 BDNF 通路的影响，将 BeWo 细胞用模拟高暴露人群血液水平和混合物中主要 PFAS 化合物的 PFAS 混合物在 0.01、0.1、1 和 10 μM 浓度下进行处理。通过 Western blot 检测 pro-BDNF 水平和 TrkB 受体的磷酸化变化。
在人胎盘的早孕期，TrkB 和 p75 受体主要定位于合体滋养层和细胞滋养层细胞。在足月时，TrkB 和 p75 受体主要存在于胎盘绒毛间质中。在足月时，滋养细胞中的 TrkB 受体染色减少，而 p75 受体染色为阴性。TrkB 受体局限于核和核周空间，磷酸化发生在 Tyr816 残基上。暴露于 PFOS、PFOA、PFBS 和六氟丙烯混合物并未显著影响 BDNF 水平或 TrkB 的激活（磷酸化）。与未暴露对照相比，用 1 μM 和 10 μM 的 PFNA 处理细胞会导致 TrkB 磷酸化增加，但 BDNF 水平不变。
BDNF 受体存在于人胎盘绒毛的不同区域，表明 BDNF 信号在胎盘发育中有不同的功能。我们的研究结果表明，PFOS、PFOA、PFBS 和 PFAS 混合物对胎盘滋养细胞中 BDNF 通路没有破坏作用，但可能受到 PFNA 暴露的影响。需要进一步研究 PFAS 如何影响胎儿神经发育过程中的其他关键信号通路。
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