Mechanotransduction activity facilitates hair cell toxicity caused by the heavy metal cadmium

Abstract

12Hair cells are sensitive to many insults including environmental toxins such as 13 heavy metals. We show here that cadmium can consistently kill hair cells of the 14 zebrafish lateral line. Disrupting hair cell mechanotransduction genetically or 15 pharmacologically significantly reduces the amount of hair cell death seen in response 16 to cadmium, suggesting a role for mechanotransduction in this cell death process, 17 possibly as a means for cadmium uptake into the cells. Likewise, when looking at 18 multiple cilia-associated gene mutants that have previously been shown to be resistant 19 to aminoglycoside-induced hair cell death, resistance to cadmium-induced hair cell 20 death is only seen in those with mechanotransduction defects. In contrast to what was 21 seen with mechanotransduction, significant protection was not consistently seen from 22 other ions previously shown to compete for cadmium uptake into cells or tissue 23 including zinc and copper. These results show that functional mechanotransduction 24 activity is playing a significant role in cadmium-induced hair cell death. 25

The role of calcium, Akt and ERK signaling in cadmium-induced hair cell death

“…Calmodulin inhibition has also previously been shown to inhibit rapid apical endocytosis in hair cells, a process dependent on mechanotransduction activity (Seiler and Nicolson, 1999). Inhibiting mechanotransduction can protect against cadmium-induced hair cell death potentially by impairing cadmium influx into hair cells (Schmid et al, 2020). We therefore wanted to distinguish between whether calmodulin inhibition was affecting mechanotransduction and cadmium uptake or the actual cell death process once cadmium was in the cell.…”

“…However, these experiments are complicated in hair cells by the fact that calmodulin inhibition also inhibits rapid apical endocytosis in hair cells, a process dependent on mechanotransduction activity (Seiler and Nicolson, 1999). As inhibiting mechanotransduction activity is known to inhibit cadmium-induced hair cell death (Schmid et al, 2020) we cannot definitively say that calmodulin inhibition is working directly on the cell death process. Particularly as calmodulin inhibition can no longer protect against cadmium-induced hair cell death when the inhibitor is added after cadmium treatment rather than as a cotreatment.…”

“…Multiple studies have found a link between blood or urinary cadmium levels and hearing or balance impairment (Choi and Park, 2017; Choi et al, 2012; Dalton et al, 2020; Huh et al, 2018; Jung, 2019; Kang et al, 2018; Min et al, 2012; Shargorodsky et al, 2011; Wang et al, 2020). Studies have also found hearing loss and/or hair cell death in mammals and fish exposed to cadmium (Faucher et al, 2006; Kim et al, 2008; Liu et al, 2014; Low and Higgs, 2015; Montalbano et al, 2018; Ozcaglar et al, 2001; Schmid et al, 2020; Sonnack et al, 2015). However, the mechanisms by which cadmium kills hair cells remain largely unknown beyond reactive oxygen species generation playing a role (Kim et al, 2008).…”

“…Hair cells of the zebrafish lateral line have been shown to be functionally, molecularly and morphologically similar to mammalian hair cells (Nicolson, 2005; Whitfield, 2002). We have previously shown that cadmium causes reliable hair cell death in the zebrafish lateral line in a dose dependent manner (Schmid et al, 2020). In this study we found that co-treatment but not posttreatment of a calmodulin inhibitor with cadmium could significantly protect against cadmium-induced hair cell death.…”

Mechanotransduction Activity Facilitates Hair Cell Toxicity Caused by the Heavy Metal Cadmium

“…We thank Amber-Lynn Lachowicz for zebrafish care. This manuscript has been released as a Pre-print at bioRxiv (Schmid et al, 2019).…”