• Enhanced adsorption of tetrabromobisphenol a (TBBPA) on cosmetic-derived plastic microbeads and combined effects on zebrafish

      Yu, Yunjiang; Ma, Ruixue; Qu, Han; Zuo, You; Yu, Ziling; Hu, Guocheng; Li, Zongrui; Chen, Haibo; Lin, Bigui; Wang, Bin; et al. (PERGAMON-ELSEVIER SCIENCE LTD, 2020-06-20)
      Microplastics (MPs) pollution and its potential environmental risks have drawn increasing concerns in recent years. Among which, microbeads in personal care and cosmetic products has becoming an emerging issue for their abundance as well as the knowledge gaps in their precise environmental behaviors in freshwater. The present study investigated the sorption process of tetrabromobisphenol A (TBBPA), the most widely applied and frequently encountered flame retardant in aquatic environments, on two sources of polyethylene (PE) particles (pristine PE particles and microbeads isolated from personal care and cosmetic products). Significantly enhanced adsorption capacity of microbeads was observed with up to 5-folds higher than the pristine PE particles. The sorption efficiency was also governed by solution pH, especially for the cosmetic-derived microbeads, indicating the strong adsorption of TBBPA on PE was dominated by both hydrophobic and electrostatic interactions. Additionally, combined effects on redox status of zebrafish were evaluated with two environmental relevant concentrations of PE particles (0.5 and 5 mg L-1) using integrated biomarker response (IBR) index through a 14-d exposure. Co-exposure induced significant antioxidative stress than either PE or TBBPA alone when exposed to 0.5 mg L-1 of MPs. After 7-d depuration, the IBR value for combination treatments [TBBPA + PE (L)] was 3-fold compared with that in MP-free groups, indicating the coexistence might exert a prolonged adverse effects on aquatic organisms. These results highlight the probability of risk from microbead pollution in freshwater, where toxic compounds can be adsorbed on microbeads in a considerable amount resulting in potential adverse effects towards aquatic organisms.
    • Failure to identify modifiers of NEBULIN-related nemaline myopathy in two pre-clinical models of the disease

      Qiu, Boyang; Ruston, Julie; Granzier, Henk; Justice, Monica J; Dowling, James J; Univ Arizona, Dept Physiol (COMPANY BIOLOGISTS LTD, 2019-09-18)
      Nemaline myopathy is a rare neuromuscular disorder that affects 1 in 50,000 live births, with prevalence as high as 1 in 20,000 in certain populations. 13 genes have been linked to nemaline myopathy (NM), all of which are associated with the thin filament of the muscle sarcomere. Of the 13 associated genes, mutations in NEBULIN (NEB) accounts for up to 50% of all cases. Currently, the disease is incompletely understood and there are no available therapeutics for patients. To address this urgent need for effective treatments for patients affected by NM, we conducted a large scale chemical screen in a zebrafish model of NEB-related NM and an N-ethyl-N-nitrosourea (ENU)-based genetic screen in a mouse model of NEB exon 55 deletion, the most common NEB mutation in NM patients. Neither screen was able to identify a candidate for therapy development, highlighting the need to transition from conventional chemical therapeutics to gene-based therapies for the treatment of NM.
    • Phenotyping an adult zebrafish lamp2 cardiomyopathy model identifies mTOR inhibition as a candidate therapy

      Dvornikov, Alexey V; Wang, Mingmin; Yang, Jingchun; Zhu, Ping; Le, Tai; Lin, Xueying; Cao, Hung; Xu, Xiaolei; Univ Arizona, Dept Cellular & Mol Med (ELSEVIER SCI LTD, 2019-08-01)
      Adult zebrafish is an emerging vertebrate model for studying genetic basis of cardiomyopathies; but whether the simple fish heart can model essential features of hypertrophic cardiomyopathy (HCM) remained unknown. Here, we report a comprehensive phenotyping of a lamp2 knockout (KO) mutant. LAMP2 encodes a lysosomal protein and is a causative gene of Danon disease that is characterized by HCM and massive autophagic vacuoles accumulation in the tissues. There is no effective therapy yet to treat this most lethal cardiomyopathy in the young. First, we did find the autophagic vacuoles accumulation in cardiac tissues from lamp2 KO. Next, through employing a set of emerging phenotyping tools, we revealed heart failure phenotypes in the lamp2 KO mutants, including decreased ventricular ejection fraction, reduced physical exercise capacity, blunted beta-adrenergic contractile response, and enlarged atrium. We also noted changes of the following indices suggesting cardiac hypertrophic remodeling in lamp2 KO: a rounded heart shape, increased end-systolic ventricular volume and density of ventricular myocardium, elevated actomyosin activation kinetics together with increased maximal isometric tension at the level of cardiac myofibrils. Lastly, we assessed the function of lysosomal-localized mTOR on the lamp2-associated Danon disease. We found that haploinsufficiency of mtor was able to normalize some characteristics of the lamp2 KO, including ejection fraction, beta-adrenergic response, and the actomyosin activation kinetics. In summary, we demonstrate the feasibility of modeling the inherited HCM in the adult zebrafish, which can be used to develop potential therapies.