Prenatal exposure to neurotoxicants dieldrin or lindane alters tert-butylbicyclophosphorothionate binding to GABA(A) receptors in fetal rat brainstem.
GABA acts as a trophic signal for cultured embryonic rat monoamine neurons by activating GABA(A) receptors. These effects are blocked by the organochlorine insecticide dieldrin and the classic GABA(A) antagonist bicuculline. Both dieldrin and another organochlorine insecticide, lindane, block the effects of GABA on the GABA(A) receptor by binding directly to the Cl- channel. Therefore, prenatal exposure to these chemicals could lead to disturbances in the trophic actions of GABA on monoamine neurotransmitter systems in the embryonic brain and produce alterations in GABA(A) receptor expression and function. Effects of daily prenatal exposure to organochlorine insecticide (dieldrin or lindane) or bicuculline from embryonic day (E)12-17 were determined in brains of E17 fetal rats using t-[35S]butyl-bicyclophosphorothionate ([35S]TBPS) binding. This radioligand was chosen because, like organochlorine insecticides, it binds directly to GABA(A) receptor/Cl- channels. [35S]TBPS binding was analyzed in extensively washed membranes from E17 brainstem and whole brain with the brainstem removed ('rest of brain') at a TBPS concentration that approximated the KD determined in [35S]TBPS saturation binding experiments performed on normal E17 rat brainstem. In utero exposure to dieldrin, lindane, or bicuculline from E12-E17 caused a significant reduction in the amount of [35S]TBPS binding in E17 brainstem compared to vehicle-injected controls, but had no significant effect on 'rest of brain'. These data suggest that in utero exposure to organochlorine insecticides that act as GABA(A) antagonists negatively regulate expression of GABAA receptors in fetal brainstem. If these effects persist, they could lead to disturbances in postnatal functions of the ascending GABAergic system, possibly with behavioral consequences.
Brannen
K C
KC
Curriculum in Toxicology, University of North Carolina, Chapel Hill, USA.
Devaud
L L
LL
Liu
J
J
Lauder
J M
JM
D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000633:toxicity; D001933:Brain Stem / Q000187:drug effects* / Q000196:embryology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism*; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism; D004026:Dieldrin / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D018756:GABA Antagonists / Q000008:administration & dosage / Q000633:toxicity; D005865:Gestational Age; D001556:Hexachlorocyclohexane / Q000008:administration & dosage / Q000633:toxicity*; D008431:Maternal-Fetal Exchange; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D018756:GABA Antagonists; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D011963:Receptors, GABA-A; D001556:Hexachlorocyclohexane; C037476:tert-butylbicyclophosphorothionate; D004026:Dieldrin; D001640:Bicuculline