Long‐term exposure to dieldrin reduces γ‐aminobutyric acid type A and N‐methyl‐D‐aspartate receptor function in primary cultures of mouse cerebellar granule cells

Abstract

The organochlorine pesticide dieldrin is a persistent organic pollutant that accumulates in the fatty tissue of living organisms. In mammals, it antagonizes the GABAA receptor, producing convulsions after acute exposure. Although accumulation in human brain has been reported, little is known about the effects of long‐term exposure to dieldrin in the nervous system. Homeostatic control of the balance between excitation and inhibition has been reported when neuronal activity is chronically altered. We hypothesized that noncytotoxic concentrations of dieldrin could decrease glutamatergic neurotransmission as a consequence of a prolonged reduction in GABAA receptor function. Long‐term exposure of primary cerebellar granule cell cultures to 3 μM dieldrin reduced the GABAA receptor function to 55% of control, as measured by the GABA‐induced 36Cl− uptake. This exposure produced a significant reduction (∼35%) of the NMDA‐induced increase in [Ca2+]i and of the [3H]MK‐801 binding, which was not accompanied by a reduction in the NMDA receptor subunit NR1, as determined by Western blot. Consistent with the decreased NMDA receptor function, dieldrin‐treated cultures were insensitive to an excitotoxic stimulus induced by exposure to high potassium. In summary, we report that the chronic reduction of GABAA receptor function induced by dieldrin decreases the number of functional NMDA receptors, which may be attributable to a mechanism of synaptic scaling. These effects could underlie neural mechanisms involved in cognitive impairment produced by low‐level exposure to dieldrin. © 2007 Wiley‐Liss, Inc.

Defining and modeling known adverse outcome pathways: Domoic acid and neuronal signaling as a case study

“…Although our TP/AOP has focused on excitotoxicity, many chemicals specifically disrupt inhibitory pathways, which will have consequences for the TP/AOP. For example, Babot et al [69] found that reduction of GABA(A) receptor function by dieldrin, an organochlorine insecticide, was followed by a decrease in NMDA receptor function as a compensatory response; and RDX, an explosive compound that causes seizures, has been shown to disrupt GABAergic signaling [125]. Application of the TP/AOP will not only enable us to better resolve the pathway/mechanisms/ risks for domoic acid, but similar assessments can be carried out for other chemicals that impact different points in the TP.…”

“…These culture systems are enriched in glutamatergic, cholinergic, and GABA-ergic neurons. The neurons mature at 6 to 10 days in culture, expressing functional receptors for NMDA and kainate [54,57,59,61,69] and releasing glutamate under depolarization [53]. When glutamate surpasses a concentration threshold, cell death occurs by a mechanism including NMDA receptors [53] or oxidative stress [54].…”

Pesticides and Herbicides

“…However, future research was recommended to provide similar exposures and outcomes to improve interpretation. Babot et al (2007) found that long-term exposure to dieldrin modified glutamatergic neurotransmission as a consequence of the prolonged decrease in γ-aminobutyric acid type A and N-methyl-D-aspartate receptor function in primary cultures of mouse cerebellar granule cells. Silver catfish (Rhamdia quelen) exposed for 96 hours to glyphosate presented an increase in the production of thiobarbituric acid reactive substances (TBARS) in muscle tissue, whereas the brain showed a decrease in TBARS (Glusczak et al, 2007).…”

Adverse Outcome Pathway on binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain

“…Banerjee et al (1999) reported functional modulation of GABAA receptors by Zn2+, pentobarbital, neuroactive steroid alphaxalone, and flunitrazepam in the cerebral cortex and cerebellum of rats undergoing status epilepticus induced by pilocarpine. Babot et al (2007) measured the reduction in mouse GABAA receptor function by 3 μM dieldrin using the GABA-induced 36Cl-uptake method. reviewed evidence for GABAA receptors in human and mammalian brains, whereas Narahashi (1996) and Costa (2015) reviewed organochlorine and some pyrethroid compounds as insecticides with the target site of chloride channel.…”