No abstract

Sertraline hydrochloride is a commonly prescribed antidepressant medication that acts by amplifying serotonin signaling. Numerous studies have suggested that children of women  taking sertraline during pregnancy have an increased risk of developmental defects. Resolving the degree of risk for human fetuses requires comprehensive knowledge of the pathways affected by this drug. We utilized a Drosophila melanogaster model system to assess the effects of sertraline throughout development. Ingestion of sertraline by females did not affect their fecundity or embryogenesis in their progeny. However, larvae that consumed sertraline experienced delayed developmental progression and reduced survival at all stages of development. Genetic experiments showed that these effects were mostly independent of aberrant extracellular serotonin levels. Using an ex vivo imaginal disc culture system, we showed that mitotically active sertraline-treated tissues accumulate DNA double-strand breaks and undergo apoptosis at increased frequencies. Remarkably, the sertraline-induced genotoxicity was partially rescued by co-incubation with ascorbic acid, suggesting that sertraline induces oxidative DNA damage. These findings may have implications for the biomedicine of sertraline-induced birth defects.

Piezo1 is a stretch-gated ion channel required for mechanosensation in many organ systems. Recent findings point to a new role for Piezo1 in the gut, suggesting that it is a sensor of microbial single-stranded RNA (ssRNA) rather than mechanical force. If true, this would redefine the scope of Piezo biology. Here, we sought to replicate the central finding that fecal ssRNA is a natural agonist of Piezo1. While we observe that fecal extracts and ssRNA can stimulate calcium influx in certain cell lines, this response is independent of Piezo1. Additionally, sterilized dietary extracts devoid of gut biome RNA show similar cell line-specific stimulatory activity to fecal extracts. Together, our data highlight potential confounds inherent to gut-derived extracts, exclude Piezo1 as a receptor for ssRNA in the gut, and support a dedicated role for Piezo channels in mechanosensing.

Piezo1 is a stretch-gated ion channel required for mechanosensation in many organ systems. Recent provocative findings describe a new role for Piezo1 in the gut, suggesting that it is a sensor of microbial single-stranded RNA (ssRNA) rather than mechanical force. If true, this would redefine the scope of Piezo biology. Here, we sought to replicate the central finding that fecal ssRNA is a natural agonist of Piezo1. While we observed that fecal extracts and ssRNA stimulate calcium influx in certain cell lines, this response was independent of Piezo1. Additionally, sterilized dietary extracts devoid of gut biome RNA showed similar cell line-specific stimulatory activity to fecal extracts. Together, our data highlight potential confounds inherent to gut-derived extracts, exclude Piezo1 as a receptor for ssRNA in the gut, and support a dedicated role for Piezo channels in mechanosensing.