Scott, Ashley Jennie

Background: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. Methods: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. Results: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. Conclusions: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

Two out of every thousand newborns are born deaf or hard of hearing. Sixty percent of hearing loss has an identifiable genetic cause. One of the most common forms of genetic hearing loss is Pendred syndrome. Disease causing genetic alterations or pathogenic variants in SLC26A4 are associated with Pendred Syndrome, a disorder characterized by bilateral sensorineural hearing loss and occasionally thyroid goiter. Patients with SLC26A4 pathogenic variants have an enlarged vestibular aqueduct, a malformation of the temporal bone. Pendrin, the protein product of SLC26A4 , is a solute carrier. Pendrin is expressed in the inner ear, thyroid, and kidney. In the inner ear, pendrin modulates the transport of bicarbonate and chloride, allowing bicarbonate to leave the supporting cells of the inner ear and chloride to enter. This helps maintain a relatively neutral pH environment in the inner ear. It is not known how the abnormal SLC26A4 protein products modulate hearing loss and contribute to temporal bone abnormalities. The goal of this study was to model SLC26A4 associated genetic hearing loss in zebrafish and elucidate a mechanism responsible for hearing loss in patients with pathogenic variants in SLC26A4 . To model the human condition, slc26a4 mutations in zebrafish were generated via transcription activator like effector nucleases (TALENs) at the site of the the most common SLC26A4 pathogenic variants. We obtained a 23bp deletion mutation in exon 10 of slc26a4 . We hypothesized that fish with biallelic slc26a4 mutations would closely recapitulate the human phenotype and have significant hearing loss and structural ear malformations. To test for deafness in zebrafish, we developed a hearing assessment which exposes larval or adult fish to specific sound stimuli while recording startle responses. To quantitatively study the slc26a4 mutant ear phenotype, we took measurements of the posterior and anterior otolith area and the ear area using bright field microscopy. Results indicate that homozygous embryos tested at 5 days post fertilization, the day of hearing onset in zebrafish, have hearing that was not different that wildype, however adult fish with two copies of mutated slc26a4 have frequency specific reduced responses at 400 Hz, 80db. These results indicate that slc26a4 mutants have progressive frequency specific hearing loss. Bright field imaging and measurement analysis showed that slc26a4 mutant larvae have significantly smaller standardized posterior otolith areas, anterior otolith areas, and ear areas on average compared to wildtype at 5dpf. This closely matches the human phenotype, as humans with SLC26A4 pathogenic variants may have progressive hearing loss and temporal bone abnormalities. Support or Funding Information Mayo Center for Individualized Medicine Mayo Clinic Department of Otorhinolaryngology NIH 5R25GM075148‐11 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .