Browsing by Author "Feng, Liping"

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Open Access
Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion.
(eLife, 2022-06-07) Zhang, Yang; Liang, Pengfei; Yang, Liheng; Shan, Ke Zoe; Feng, Liping; Chen, Yong; Liedtke, Wolfgang; Coyne, Carolyn B; Yang, Huanghe
TMEM16F, a Ca²⁺-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization, however, how TMEM16F is activated during cell fusion is unclear. Here, using trophoblasts as a model for cell fusion, we demonstrate that Ca²⁺ influx through the Ca²⁺ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and plays a role in subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. We also show that TRPV4 and TMEM16F are functionally coupled within Ca²⁺ microdomains in a human trophoblast cell line using patch-clamp electrophysiology. Pharmacological inhibition or gene silencing of TRPV4 hinders TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and one of the physiological activation mechanisms of TMEM16F in human trophoblasts, thus providing us with novel strategies to regulate CaPLSase activity as a critical checkpoint of physiologically and disease-relevant cell fusion events.
Embargo
In Vivo Investigation of Perinatal PFAS Exposure through Drinking Water on Birth Outcomes and Neurodevelopment in Offspring
(2023) Zhu, Tianyi
Pittsboro, North Carolina, has been burdened by exceptionally high concentration of per- and polyfluoroalkyl substances (PFAS) contamination in drinking water. Our previous study reported that perinatal exposure to a PFAS mixture mimicking the PFAS levels in Pittsboro, NC drinking water led to gestational hypertension and lower fetal weights in rabbits. However, there has been significant gaps in literature uncovering the toxicity and biological processes and physiological mechanisms affected by this PFAS mixture, which hindered researchers and policy makers articulate the harm of PFAS chemicals to communities like Pittsboro, NC. This study, therefore, aims to supply evidence that helps establish a causal relationship between in utero exposure to this PFAS mixture and birth outcomes, focusing on the neurodevelopment of offspring in rats. Various neurobehavioral tests, molecular, and pathological examinations have been accomplished to uncover physiological alterations associated with maternal PFAS mixture exposure and underlying mechanisms. Our research discovered that maternal PFAS exposure led to a significant delay in pup locomotor development in a sex-specific manner and reduced brain volume in postnatal day 1 (PND 1) pups. Transcriptome analysis identified 564 differentially expressed genes (DEGs) in cerebellum samples collected from the low-dose PFAS group. The DEGs are enriched in mitochondrial and metabolic pathways or pathogenetic ontologies suggest abnormal neurodevelopment including locomotor signals.
Open Access
Infection-induced thrombin production: a potential novel mechanism for preterm premature rupture of membranes (PPROM).
(American journal of obstetrics and gynecology, 2018-07) Feng, Liping; Allen, Terrence K; Marinello, William P; Murtha, Amy P
Preterm premature rupture of membranes is a leading contributor to maternal and neonatal morbidity and death. Epidemiologic and experimental studies have demonstrated that thrombin causes fetal membrane weakening and subsequently preterm premature rupture of membranes. Although blood is suspected to be the likely source of thrombin in fetal membranes and amniotic fluid of patients with preterm premature rupture of membranes, this has not been proved. Ureaplasma parvum is emerging as a pathogen involved in prematurity, which includes preterm premature rupture of membranes; however, until now, prothrombin production that has been induced directly by bacteria in fetal membranes has not been described.This study was designed to investigate whether Ureaplasma parvum exposure can induce prothrombin production in fetal membranes cells.Primary fetal membrane cells (amnion epithelial, chorion trophoblast, and decidua stromal) or full-thickness fetal membrane tissue explants from elective, term, uncomplicated cesarean deliveries were harvested. Cells or tissue explants were infected with live Ureaplasma parvum (1×105, 1×106 or 1×107 colony-forming units per milliliter) or lipopolysaccharide (Escherichia coli J5, L-5014; Sigma Chemical Company, St. Louis, MO; 100 ng/mL or 1000 ng/mL) for 24 hours. Tissue explants were fixed for immunohistochemistry staining of thrombin/prothrombin. Fetal membrane cells were fixed for confocal immunofluorescent staining of the biomarkers of fetal membrane cell types and thrombin/prothrombin. Protein and messenger RNA were harvested from the cells and tissue explants for Western blot or quantitative reverse transcription polymerase chain reaction to quantify thrombin/prothrombin protein or messenger RNA production, respectively. Data are presented as mean values ± standard errors of mean. Data were analyzed using 1-way analysis of variance with post hoc Dunnett's test.Prothrombin production and localization were confirmed by Western blot and immunostainings in all primary fetal membrane cells and tissue explants. Immunofluorescence observations revealed a perinuclear localization of prothrombin in amnion epithelial cells. Localization of prothrombin in chorion and decidua cells was perinuclear and cytoplasmic. Prothrombin messenger RNA and protein expression in fetal membranes were increased significantly by Ureaplasma parvum, but not lipopolysaccharide, treatments in a dose-dependent manner. Specifically, Ureaplasma parvum at a dose of 1×107 colony-forming units/mL significantly increased both prothrombin messenger RNA (fold changes in amnion: 4.1±1.9; chorion: 5.7±4.2; decidua: 10.0±5.4; fetal membrane: 9.2±3.0) and protein expression (fold changes in amnion: 138.0±44.0; chorion: 139.6±15.1; decidua: 56.9±29.1; fetal membrane: 133.1±40.0) compared with untreated control subjects. Ureaplasma parvum at a dose of 1×106 colony-forming units/mL significantly up-regulated prothrombin protein expression in chorion cells (fold change: 54.9±5.3) and prothrombin messenger RNA expression in decidua cells (fold change: 4.4±1.9).Our results demonstrate that prothrombin can be produced directly by fetal membrane amnion, chorion, and decidua cells. Further, prothrombin production can be stimulated by Ureaplasma parvum exposure in fetal membranes. These findings represent a potential novel underlying mechanism of Ureaplasma parvum-induced rupture of fetal membranes.
Open Access
Levels of Urinary Metabolites of Organophosphate Flame Retardants, TDCIPP, and TPHP, in Pregnant Women in Shanghai.
(J Environ Public Health, 2016) Feng, Liping; Ouyang, Fengxiu; Liu, Liangpo; Wang, Xu; Wang, Xia; Li, Yi-Ju; Murtha, Amy; Shen, Heqing; Zhang, Junfeng; Zhang, Jun Jim
Flame retardants are widely used in consumer products to reduce their flammability. Previously used flame retardants have been sequentially banned due to their environmental and human toxicity. Currently, tris(1,3-dichloropropyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP) are among the most commonly used flame retardants. TDCIPP and TPHP are reproductive toxins and have carcinogenic, neurotoxic, and endocrine-disrupting properties. Although high levels of TDCIPP and TPHP have been found in drinking water, seawater, and office air in China, data regarding human exposure are lacking. In this study, we assessed the level of urinary TPHP and TDCIPP metabolites (DPHP and BDCIPP, resp.) in a cohort of pregnant women (N = 23) from Shanghai, China, using liquid chromatography-tandem mass spectrometry. DPHP were detected in 100% urine samples, while only four urine samples had detectable level of BDCIPP in this cohort (17% detected). Geometric means of DPHP and BDCIPP concentrations were 1.1 ng/mL (interquartile range [IQR]: 0.6, 1.5 ng/mL) and 1.2 ng/mL (IQR: 0.6, 2.2 ng/mL), respectively. In this small cohort, urinary DPHP and BDCIPP levels were not significantly correlated with miscarriages, neonatal birthweight, gestational diabetes, or maternal age. These data suggest that exposure to TPHP is widespread, and they demonstrate the feasibility of using urinary biomarkers to measure exposures to modern flame-retardant chemicals.
Open Access
Longitudinal intravital imaging of mouse placenta.
(Science advances, 2024-03) Zhu, Xiaoyi; Huang, Qiang; Jiang, Laiming; Nguyen, Van-Tu; Vu, Tri; Devlin, Garth; Shaima, Jabbar; Wang, Xiaobei; Chen, Yong; Ma, Lijun; Xiang, Kun; Wang, Ergang; Rong, Qiangzhou; Zhou, Qifa; Kang, Yubin; Asokan, Aravind; Feng, Liping; Hsu, Shiao-Wen D; Shen, Xiling; Yao, Junjie
Studying placental functions is crucial for understanding pregnancy complications. However, imaging placenta is challenging due to its depth, volume, and motion distortions. In this study, we have developed an implantable placenta window in mice that enables high-resolution photoacoustic and fluorescence imaging of placental development throughout the pregnancy. The placenta window exhibits excellent transparency for light and sound. By combining the placenta window with ultrafast functional photoacoustic microscopy, we were able to investigate the placental development during the entire mouse pregnancy, providing unprecedented spatiotemporal details. Consequently, we examined the acute responses of the placenta to alcohol consumption and cardiac arrest, as well as chronic abnormalities in an inflammation model. We have also observed viral gene delivery at the single-cell level and chemical diffusion through the placenta by using fluorescence imaging. Our results demonstrate that intravital imaging through the placenta window can be a powerful tool for studying placenta functions and understanding the placental origins of adverse pregnancy outcomes.
Open Access
Prenatal and perinatal exposure to Per- and polyfluoroalkyl substances (PFAS)-contaminated drinking water impacts offspring neurobehavior and development.
(The Science of the total environment, 2024-03) Marchese, Melissa J; Zhu, Tianyi; Hawkey, Andrew B; Wang, Katherine; Yuan, Emi; Wen, Jinchen; Be, Sara E; Levin, Edward D; Feng, Liping
Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants ubiquitous in the environment and humans. In-utero PFAS exposure is associated with numerous adverse health impacts. However, little is known about how prenatal PFAS mixture exposure affects offspring's neurobehavioral function. This study aims to determine the causal relationship between in-utero PFAS mixture exposure and neurobehavioral changes in Sprague-Dawley rat offspring. Dams were exposed via drinking water to the vehicle (control), an environmentally relevant PFAS mixture, or a high-dose PFAS mixture. The environmentally relevant mixture was formulated to resemble measured tap water levels in Pittsboro, NC, USA (10 PFAS compounds; sum PFAS =758.6 ng/L). The high-dose PFAS load was 3.8 mg/L (5000×), within the range of exposures in the experimental literature. Exposure occurred seven days before mating until birth. Following exposure to PFAS-laden water or the vehicle during fetal development, neurobehavioral toxicity was assessed in male and female offspring with a battery of motor, cognitive, and affective function tests as juveniles, adolescents, and adults. Just before weaning, the environmentally relevant exposure group had smaller anogenital distances compared to the vehicle and high-dose groups on day 17, and males in the environmentally relevant exposure group demonstrated lower weights than the high-dose group on day 21 (p < 0.05). Reflex development delays were seen in negative geotaxis acquisition for both exposure groups compared to vehicle-exposed controls (p = 0.009). Our post-weaning behavioral measures of anxiety, depression, and memory were not found to be affected by maternal PFAS exposure. In adolescence (week five) and adulthood (week eight), the high PFAS dose significantly attenuated typical sex differences in locomotor activity. Maternal exposure to an environmentally relevant PFAS mixture produced developmental delays in the domains of pup weight, anogenital distance, and reflex acquisition for rat offspring. The high-dose PFAS exposure significantly decreased typical sex differences in locomotor activity.
Open Access
The Neurodevelopmental Effects of PFAS Exposure through Drinking Water
(2022) Marchese, Melissa June
Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in the environment and in humans. One local population facing disproportionate PFAS exposure risk through their drinking water was Pittsboro, NC residents. In utero PFAS exposure is associated with an array of long-term health effects; however, the mechanism of toxicity is poorly understood. The aim of this study is to determine the causal relationship between in utero PFAS mixture exposure and cognitive deficits, emotional dysfunction, and behavioral dysregulation in rats. Using animal models, this study addresses the neurodevelopmental effects of gestational exposure to clearly defined PFAS concentrations seen in Pittsboro’s drinking water and a 5,000-fold concentration as the positive control. To quantitatively assess toxicity, animal subjects exposed to PFAS-laden drinking water during fetal development underwent a battery of assessments from an established behavioral testing framework. Dams exposed to the high-dose mixture yielded smaller litters on average. Offspring in the low-dose group of environmental relevance demonstrated significantly smaller weights (p<0.05) and smaller anogenital distances on average just prior to weaning (PND 21). In the behavioral battery, low and high-dose-exposed rats made fewer attempts to explore different arms of the elevated plus maze, indicating a heightened anxiety response. In the figure-8 maze, males in the high-dose group displayed hyperactivity compared to the other groups. These findings suggest that maternal PFAS exposure may be able to cause diminished fertility, small pup size, increased anxiety, and hyperactivity in rats. However, continued investigation is necessary to obtain sufficient statistical power.