Global occurrence and probabilistic environmental health hazard assessment of per- and polyfluoroalkyl substances (PFASs) in groundwater and surface waters.

Per- and polyfluoroalkyl substances (PFASs) have been used in consumer and military products since the 1950s but are increasingly scrutinized worldwide because of inherent chemical properties, environmental contamination, and risks to public health and the environment. The United States Environmental Protection Agency (USEPA) identified 24 PFASs of interest for further study and possible regulation. We examined 371 peer-reviewed studies published since 2001 to understand the occurrence and distribution of 24 priority PFASs in global surface waters and groundwater. We identified 77,541 and 16,246 data points for surface waters and groundwater, respectively, with total PFAS concentrations ranging from low pg/L to low mg/L levels. Most data were from Asia, Europe, and North America with some reports from Oceania. PFAS information from other geographic regions is lacking. PFASs levels are consistently higher in rivers and streams followed by lakes and reservoirs and then coastal and marine systems. When sufficient data were available, probabilistic environmental hazard assessments (PEHAs) were performed from environmental exposure distributions (EEDs) to identify potential exceedances of available guideline values for each compound by matrix, region, and aquatic system. Specifically, exceedances of USEPA drinking water lifetime health advisory levels were up to 74% for PFOS in groundwater from Oceania and 69% for PFOA in North American groundwater. Our findings support selection of environmentally relevant experimental treatment levels for future toxicology, ecotoxicology and bioaccumulation studies, and potable source water exposure investigations, while highlighting PFASs and major geographic locations requiring additional study and inclusion in global monitoring and surveillance campaigns.

8:8 Perfluoroalkyl phosphinic acid affects neurobehavioral development, thyroid disruption, and DNA methylation in developing zebrafish.

Recent studies have reported potential neurotoxicity and epigenetic alteration associated with exposure to several per- and polyfluoroalkyl substances (PFASs). However, such information is limited to a few compounds (e.g., perfluorooctane sulfonate), primarily based on rodent experiments, and the underlying toxicological mechanism(s) for many PFAS in the environment remain poorly understood. In the present study, we investigated 8:8 perfluoroalkyl phosphinic acid (8:8 PFPiA), an under-studied PFAS with high persistency in the environment and biota, using the zebrafish model. We exposed zebrafish embryos (<4 hpf) to various concentrations of 8:8 PFPiA (0, 0.0116, 0.112, 0.343, 1.34, 5.79 µM) for 144 h. Although there was no significant change in survival, hatchability and malformations, zebrafish locomotor speed at 120 h significantly decreased in dark photoperiod. At 144 h, several genes related to thyroid hormones that are essential for neurodevelopment, including corticotropin releasing hormone b (crhb), iodothyronine deiodinase 3a (dio3a), thyroid-stimulating hormone receptor (tshr) and nkx2 homeobox1 (nkx 2.1), were up-regulated by 8:8 PFPiA at 5.79 µM. 8:8 PFPiA also significantly down-regulated a neurodevelopmental gene, elav like neuron-specific RNA binding protein (elavl3), at 1.34 and 5.79 µM; in addition, one oxidative stress gene was slightly but significantly up-regulated. Further, global DNA methylation was significantly decreased at higher treatment levels, identifying effects of 8:8 PFPiA on epigenetic regulation. However, promoter DNA methylation of selected genes (dio3, tshr, nkx2.1) were not statistically altered, though dio3 methylation showed a decreasing trend with 8:8 PFPiA exposure. Our results specifically advance an understanding of molecular toxicology of PFPiA and more broadly present an approach to define diverse responses during animal alternative assessments of PFASs.

Gene Correction of LGMD2A Patient-Specific iPSCs for the Development of Targeted Autologous Cell Therapy.

Limb girdle muscular dystrophy type 2A (LGMD2A), caused by mutations in the Calpain 3 (CAPN3) gene, is an incurable autosomal recessive disorder that results in muscle wasting and loss of ambulation. To test the feasibility of an autologous induced pluripotent stem cell (iPSC)-based therapy for LGMD2A, here we applied CRISPR-Cas9-mediated genome editing to iPSCs from three LGMD2A patients to enable correction of mutations in the CAPN3 gene. Using a gene knockin approach, we genome edited iPSCs carrying three different CAPN3 mutations, and we demonstrated the rescue of CAPN3 protein in myotube derivatives in vitro. Transplantation of gene-corrected LGMD2A myogenic progenitors in a novel mouse model combining immunodeficiency and a lack of CAPN3 resulted in muscle engraftment and rescue of the CAPN3 mRNA. Thus, we provide here proof of concept for the integration of genome editing and iPSC technologies to develop a novel autologous cell therapy for LGMD2A.