Arsenic impairs embryonic lung development by modulating airway smooth muscle contractions via the calcium/calmodulin pathway
Date
2020
Authors
Hillman, Christine
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Millions of people world-wide are exposed to arsenic through contaminated water that is either consumed directly or through contaminated crops (Hughes et al., 2011). Arsenic is a naturally occurring compound that is distributed all over the world and is associated with pathologies including malignancies of nearly all body organs, cardiovascular diseases, respiratory diseases, and preterm labor with varied symptom severity depending on the source and duration of exposure (Hasan et al., 2019, Wai et al., 2017). While mechanisms have been proposed for certain pathologies including cancer, and heart disease, the mechanisms underlying arsenic-induced respiratory pathologies and poor birth outcomes are not well characterized (Ratnaike, 2003, Singh et al., 2011). The majority of arsenic toxicology research studies adulthood exposure despite the knowledge that the developing fetus is exposed to arsenic through trans placental transport when a pregnant mother is exposed to arsenic (Gerber et al., 1982). There is a gap in knowledge regarding the mechanism in which arsenic contributes to respiratory diseases, especially in regards to in utero exposure to the developing fetus (Wai et al., 2017). This research examines if arsenic affects embryonic lung development by modulating airway smooth muscle (ASM) contractions via the calcium/calmodulin contractile pathway. This pathway has been implicated in arsenic-induced pathologies of other smooth muscles such as cardiac smooth muscle and vascular smooth muscle making it a logical pathway to consider when studying respiratory pathologies with associated ASM components (Singh et al., 2011). Embryonic mouse lungs were cultured in presence and absence of arsenic and the phenotypes were assessed. This research revealed that arsenic-exposed lungs are underdeveloped in that they exhibit narrowing of the major airways of the lung in addition to fewer alveoli precursors (terminal buds). In addition, contractions of the ASM were visualized using timelapse bright field imaging which showed that arsenic-exposed lungs contract less frequently. Finally, a transgenic mouse line was used to study the calcium/calmodulin mediated contraction pathway. These mice autoflouresce when calcium binds intracellular calmodulin and emits green fluorescence which was observed over time. Peaks in fluorescence were indicative of intracellular calcium influx. The reduced frequency of calcium influx along with reduced ASM contractions and underdeveloped lungs suggests the mechanism which contributes to respiratory pathologies and poor birth outcomes associated with exposure to arsenic.
Description
Keywords
Arsenic exposure, Embryonic lung development, Airway smooth muscle contractions, Calcium/calmodulin pathway, Respiratory pathologies