In vitro organotin administration alters guinea pig cochlear outer hair cell shape and viability.
Trimethyltin (TMT) and triethyltin (TET) disrupt auditory function at doses far below those shown to be neurotoxic. In vivo studies suggest that the initial effect of TMT on hearing occurs at the inner hair cell/spiral ganglion cell synapse, while later, the outer hair cell (OHC) undergoes structural and functional damage. TET produces acute effects upon afferent neurotransmission similar to those observed following TMT, but TET's effects on OHC structure and function have not been examined. OHCs are motile elements within the cochlea, believed to modulate the sensitivity and tuning within the inner ear. Changes in OHC length may alter hearing function, and length changes have been reported following exposure to various ototoxic agents in vitro. In the present study, 77 OHCs from 45 pigmented male guinea pigs were isolated in primary culture and exposed for 90 min to concentrations between 30 microM and 1.0 mM of TMT or TET and then to bathing medium for 30 min to remove the toxicant. Significant shortening of the OHC cell body occurred at all doses to both organotins, with a mean reduction in length of 15.1 and 20.2% for 1.0 mM TMT and TET, respectively, at the end of testing; control cells were only 3.4% shorter at the end of 90 min of perfusion with bathing medium. The effect of organotin exposure on OHC volume was not consistently related to either TMT or TET concentration or altered cell length. In addition, disruption of the plasma membrane characterized by bleb formation, the forceful ejection of cytoplasm, or bursting was seen in 80% of cells exposed to 1.0 mM TET, although not TMT; lower concentrations of both organotins disrupted the cell membrane in 10-30% of cells. Membrane rupture was not reliably associated with either increased cell volume or decreased length, implicating a weakening of the plasma membrane or cortical lattice as the basis for this effect. Consistent with the irreversible structural weakening of the lateral wall, resorption of organotin-induced cytoplasmic blebs was never evidenced. Qualitatively, subcellular elements in the central core of many organotin-treated OHCs appeared pathological. These changes are similar to histopathological changes observed following in vivo organotin administration and may represent one target of acute alkyltin ototoxicity.
Clerici
W J
WJ
Department of Environmental Health Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2167.
Chertoff
M E
ME
Brownell
W E
WE
Fechter
L D
LD
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects*; D008297:Male; D009994:Osmolar Concentration; D014267:Triethyltin Compounds / Q000633:toxicity*; D014298:Trimethyltin Compounds / Q000633:toxicity*
D014267:Triethyltin Compounds; D014298:Trimethyltin Compounds; C046488:trimethyltin; C031575:triethyltin