Evaluation of developmental neurotoxicity of organotins via drinking water in rats: dimethyl tin.
Dimethyltin (DMT) is one of several organotins that are detected in domestic water supplies due to their use as plastic stabilizers for polyvinyl chloride (PVC) and chlorinated PVC (CPVC) products. A limited number of in vitro and in vivo studies suggest that DMT may produce developmental neurotoxicity; therefore, we initiated studies to evaluate long-term neurobehavioral changes in offspring following perinatal exposure. In the first study, female Sprague-Dawley rats were exposed via drinking water to DMT (0, 3, 15, 74 ppm) before mating and throughout gestation and lactation. Male offspring were tested for changes in: 1) preweaning learning in an associative runway task, 2) motor activity ontogeny, 3) spatial learning and retention in the Morris water maze as adults, 4) brain weight, 5) biochemical evidence of apoptosis, and 6) neuropathology. DMT toxicity was expressed as depressed maternal weight gain (74 ppm), and in the offspring, decreased brain weight (3, 74 ppm), decreased apoptosis (all concentrations), mild vacuolation in adult offspring (all concentrations), and slower learning in the water maze (15 ppm) due to altered spatial search patterns. In a second study, DMT exposure (same concentrations) occurred from gestational day 6 to weaning. Male and female offspring were tested. The high concentration again depressed maternal weight gain, decreased offspring birth weight and preweaning growth, and decreased brain weight. Increased and decreased apoptotic markers were measured, depending on age. Learning deficits were observed in the runway at postnatal day 11 (15, 74 ppm) and again in the adult offspring in the water maze (15 ppm). The results of both studies demonstrate a reproducible effect of 15 ppm perinatal DMT exposure on spatial learning. Changes in expression of apoptosis, brain weight, and the occurrence of neuropathological lesions also indicate potential neurotoxicity of DMT. These results were in contrast to earlier findings with monomethyl tin, for which only similar neuropathological lesions were observed. Thus, developmental neurotoxicity may be produced in offspring following gestational exposure to DMT in drinking water.
Ehman
K D
KD
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA.
Phillips
P M
PM
McDaniel
K L
KL
Barone
S
S
Moser
V C
VC
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001933:Brain Stem / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005069:Evaluation Studies as Topic; D005260:Female; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D009947:Organotin Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014881:Water Supply
D009947:Organotin Compounds