Structure-activity comparison of organotin species: dibutyltin is a developmental neurotoxicant in vitro and in vivo.
Human exposure to the organotins can occur due to their use as polyvinyl chloride heat stabilizers and as marine biocides. The consequences of this exposure for human health are unknown. We initially compared the toxicity of monomethyltin, dimethyltin, and dibutyltin to the known neurotoxicant trimethyltin using an in vitro model of neuronal development in PC12 cells. Dibutyltin, a compound traditionally thought to target the immune system, was the most potent neurotoxicant. Dibutyltin significantly inhibited neurite outgrowth and caused cell death at concentrations approximately 40-fold lower than the lowest toxic concentrations of trimethyltin. Dimethyltin was less potent than trimethyltin and monomethyltin was not toxic at any concentration examined. These results suggested the importance of prioritizing in vivo neurotoxicity testing with dibutyltin. To accomplish this, pregnant rats were dosed orally with low levels of dibutyltin from gestational day 6 through weaning. In response to developmental dibutyltin exposure, the incidence of apoptotic cell death, measured by DNA fragmentation and TUNEL staining, was increased in the neocortex and hippocampus of postnatal day 38 offspring. No effect was observed at other ages examined.
Jenkins
Scott M
SM
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, OAQPS/ESD/REAG C404-01, Research Triangle Park, NC 27711, USA. jenkins.scott@epa.gov
Ehman
Kimberly
K
Barone
Stanley
S
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D008297:Male; D019579:Neocortex / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009947:Organotin Compounds / Q000737:chemistry / Q000633:toxicity*; D016716:PC12 Cells; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D013329:Structure-Activity Relationship; D014220:Trialkyltin Compounds / Q000633:toxicity; D014298:Trimethyltin Compounds / Q000633:toxicity
D009947:Organotin Compounds; D014220:Trialkyltin Compounds; D014298:Trimethyltin Compounds; C056189:di-n-butyltin; C046488:trimethyltin; C011559:tributyltin; D020932:Nerve Growth Factor