title: Organochlorine insecticides lindane and dieldrin and their binary mixture disturb calcium homeostasis in dopaminergic PC12 cells.
abstract: Current hypotheses link long-term environmental exposure of humans to persistent organochlorine (OC) insecticides lindane (HCH) and dieldrin (HEOD) to the development of neurodegenerative disorders, such as Parkinson's disease. Primary adverse neurological effects of these insecticides are directed at inhibition of GABA(A) and glycine receptors, although GABA-independent effects have also been reported. In this paper we describe the effect of dieldrin and a binary mixture of dieldrin and lindane on a critical parameter of neuronal function and survival, i.e., intracellular calcium homeostasis. The intracellular calcium concentration ([Ca(2+)](i)) has been monitored using real-time single-cell fluorescence microscopy in dopaminergic PC12 cells loaded with the calcium-sensitive dye Fura-2. The results demonstrate that nanomolar concentrations of dieldrin time- and concentration-dependently inhibit depolarization-evoked influx of Ca(2+). Co-exposure of PC12 cells to a mixture of dieldrin and lindane revealed an additive inhibition of the depolarization-evoked increase in [Ca(2+)](i), whereas the lindane-induced increase in basal [Ca(2+)](i) is inhibited by dieldrin. The combined findings indicate that dieldrin and binary mixtures of organochlorines affect [Ca(2+)](i) already at concentrations below commonly accepted effect concentrations and close to human internal dose levels. Consequently, current findings illustrate the need to take mixtures of OC insecticides into account in human risk assessment.
authors.affiliation: Neurotoxicology Research Group, Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands.
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Heusinkveld
authors.forename: Remco H S
authors.initials: RH
authors.lastname: Westerink
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004026:Dieldrin / Q000633:toxicity*; D016257:Fura-2; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects*; D007306:Insecticides / Q000633:toxicity*; D008856:Microscopy, Fluorescence; D016716:PC12 Cells; D051381:Rats
chemical_list: D007306:Insecticides; D001556:Hexachlorocyclohexane; D004026:Dieldrin; D002118:Calcium; D016257:Fura-2