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.

In vitrodopaminergic neurotoxicity of pesticides: a link with neurodegeneration?

“…Recent findings add to the body of evidence that pesticides from different classes and with varying chemical structures can induce neurotoxicity in vitro (Heusinkveld et al 2010;Heusinkveld & Westerink 2012;Heusinkveld et al 2013;Meijer et al 2014a). In many cases, neurotoxicity is due to mechanisms that are unrelated to the primary pesticidal mode of action.…”

“…inhibition of VGCC and GABAergic neurotransmission). We previously demonstrated additive effects on VGCC inhibition in mixtures of lindane and dieldrin (Heusinkveld & Westerink 2012) as well as mixtures of azole fungicides (Heusinkveld et al 2013). Considering the fact that these compounds share a target, it appears thus realistic that additivity may also apply for mixtures of these different classes of compounds.…”

Organochlorine pesticides and their metabolites in human breast milk from Shanghai, China

“…However, although the EDI values and even the predicted high-end daily intake values (the 99th percentile) were low, infants as the vulnerable subgroup are exposed to relatively higher doses of OCPs through consumption of more food per kilogram of body weight than adults are, and infants are more susceptible owing to their dynamic growth and developmental processes (Bennett et al 1996). In addition, the potential additive and/or synergistic effects of individual OCPs are of particular concern (Carpenter 2013;Heusinkveld and Westerink 2012;Mao and Liu 2008).…”

In vitro neurotoxic hazard characterization of different tricresyl phosphate (TCP) isomers and mixtures

“…The different assays were performed as described previously (Heusinkveld and Westerink, 2012;Heusinkveld et al, 2013).…”