Ru-pin Alicia Chi, a post-doctoral researcher at NIEHS in the Reproductive and Developmental Biology Laboratory, was given the Campion Fund Award for the best oral presentation at the recent Triangle Consortium for Reproductive Biology meeting held on February 26, 2021. Her presentation, WNK1 regulates embryo implantation in mice through PP2A-AKT (protein phosphatase A2- alpha serine/threonine protein kinase) signaling, was judged outstanding by a panel of independent scientists selected by the meeting program committee. WNK1 (with no lysine kinase 1 or lysine deficient protein kinase 1) is an atypical kinase protein that is known for its function in regulating ion homeostasis and cardiovascular development. Dr Chi, working with Dr Francesco DeMayo and colleagues in his laboratory, has shown that WNK1 is a downstream mediator of epidermal growth factor receptor (EGFR) in decidualizing human endometrial cells. Using a global kinase profiling analysis preliminary studies showed that WNK1 inhibition impaired several decidualizing events, including cell proliferation, migration and differentiation. In a mouse model with conditional WNK1 ablation from the reproductive tract she reported altered uterine morphology, endometrial hyperplasia, adenomyosis, and delay in embryo implantation. By utilizing transcriptome, proteome and interactome investigation Dr. Chi demonstrated a novel regulative role of WNK1 in the PP2A-AKT-FOXO1 (Forkhead Box O1)signaling axis. WNK1 interacts directly with PP2RIA, (protein phosphatase 2A regulation subunit A, alpha isoform) a molecule crucial for PP2A phosphatase activation. PP2A phosphatase dephosphorylates AKT, reducing its inhibitory effects on FOX01. Thus, FOX01 enters the nucleus and regulates the transcription of implantation-associated genes. Ablation of of WNK1 results in the loss of uterine FOX01 localization to the nucleus leading to dysregulation of FOXO1 -regulated genes and impairs implantation resulting in compromised fertility. These findings reveal a novel function of WNK1 in mediating implantation in mice through post-translational modulation of AKT and FOX01.
Christine Crute was given a Campion Fund Award for the best poster presentation. She is a graduate student at Duke University, Integrated Toxicology and Environmental Health Program. Her thesis advisors are Drs. Liping Feng and Susan Murphy, Nicholas School of the Environment, Integrated Toxicology and Environmental Health Program and School of Medicine, Department of Obstetrics and Gynecology. Her presentation was entitled, Maternal exposure to an environmentally relevant mixture of per-and poly-fluoroalkyl substances (PFAS) leads to adverse pregnancy outcomes in a New Zealand White rabbit model. Per-and Poly-fluoroalkyl substances are synthetic substances in commercial household products such as nonstick cookware, food packaging, stain resistant carpets and furniture. In the United States population >95% of persons have detectable PFAS in their blood due to exposure of contaminated drinking water and indoor dust. This exposure in humans is associated with adverse health effects including disruption of the endocrine system, liver and immune system toxicity as well as developmental defects. Evidence raises concerns that maternal PFAS exposure is associated with maternal hypertensive disorders, thyroid hormone disruption and fetal growth restriction. It was recently discovered that PFAS blood levels in residents in Pittsboro, NC are two to four times higher than in the genera US population. The likely cause of the high blood levels is the highly contaminated drinking water. Chrissy Chute evaluated pregnancy endpoints using New Zealand White rabbits, with placentation closer to that of human placentas compared to other animal models. The rabbits were supplied with control (no detectable PFAS levels) or PFAS contaminated drinking water formulated with PFAS to resemble levels measured in tap water from Pittsboro (10 PFAS compounds, total PFAS load=758.6 ng/). One week after drinking water exposure, dams were bred and pregnancy confirmed by ultrasound on gestational day 15. At gestational day 25 the maternal and fetal organs were directly evaluated and measured. Maternal PFAS exposure led to increased body weight (p=0.002) and liver weight(P=0.001) decreased gravid uterine weight(P=0.0005) and decreased number of fetuses. The PFAS exposed dams had small soft lesions across their uteri while two dams had late fetal resorptions which were not seen in the control dams. The placental weights from exposed dams trended heavier than control placentas ( p=0.06). There was no change in fetal body weight, crown rump length or brain weight. Maternal mean arterial blood pressure observed by indirect doppler arterial measurement at baseline and at gestational day 25 was increased compared to controls (p=0.01). Her studies are continuing to investigate the pathology of the placenta, uterus and liver of the rabbits using serum biomarker assays, hormonal measurements and related gene and protein expression.