Retinal developmental neurotoxicity of trimethyltin chloride: in terms of excitotoxicity and excitatory amino acid transporters

Trimethyltin chloride (TMT), which is an organotin compound widely used in the agricultural and industrial fields, is a well-known neurotoxicant. In particular, excitotoxicity is suspected to be an important mechanism underlying TMT toxicity; however, the effect of TMT exposure on the retina during development and the mechanisms have not been fully elucidated to date. Therefore, in this study, we exposed postnatal mice to TMT and performed a comprehensive analysis of the retina in terms of developmental abnormalities, histopathology, apoptosis, electrophysiological function, glutamate concentration, gene expression, and fluorescence immunostaining. Exposure to 0.75 and 1.5 mg/kg of TMT up to postnatal day 14 caused a decrease in body weight and length, delayed eye opening, and induced thinning of the inner nuclear layer of the retina. In addition, apoptosis was observed in the retinal layer along with b-wave changes and a decrease in retinal ganglion cell spiking activity in the micro-electroretinogram. This change was accompanied by an increase in the concentration of glutamate in the retina, upregulation of astrocyte-related genes, and increased expression of excitatory amino acid transporter (EAAT) 1 and 2. Conversely, EAAT 3, 4, and 5, located in the retinal neurons, were decreased, and this was consistent with the immunostaining results. Our results are the first to prove that TMT induces excitotoxicity and changes in EAAT expression in the retina, and this mechanism causes functional as well as morphological retinal developmental toxicity.