Non-dioxin-like PCBs inhibit [(3)H]WIN-35,428 binding to the dopamine transporter: a structure-activity relationship...

Area of Science:

• Environmental Chemistry
• Neurotoxicology
• Biochemistry

Background:

• Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are known neurotoxicants affecting the brain's dopaminergic system.
• Previous studies indicated NDL-PCBs inhibit dopamine uptake, likely via the dopamine transporter (DAT).

Purpose of the Study:

• To directly investigate NDL-PCB interaction with DAT using a specific binding assay.
• To explore the structure-activity relationship of NDL-PCBs' effects on DAT.
• To compare DAT inhibition with potential effects on vesicular monoamine transporter 2 (VMAT2).

Main Methods:

• Utilized the cocaine analogue [(3)H]WIN-35,428 binding assay with rat brain synaptosomes.
• Tested thirty different NDL-PCB congeners, including tri- to hepta-chlorinated compounds.
• Examined PCB congener selectivity for DAT versus VMAT2 inhibition.

Main Results:

• NDL-PCBs demonstrated potent inhibition of [(3)H]WIN-35,428 binding to DAT.
• Identified PCB 110 as a potent DAT inhibitor, comparable to cocaine.
• Ortho-chlorinated NDL-PCBs, especially tetra- and penta-chlorinated congeners, were most effective DAT inhibitors.
• Highly prevalent congeners in Aroclor mixtures showed significant DAT inhibition.
• Results correlated well with established neurotoxic equivalency factors (NEQs).

Conclusions:

• NDL-PCBs directly inhibit DAT, with ortho-chlorination being a key structural feature for potency.
• DAT inhibition by prevalent NDL-PCBs likely contributes to neurobehavioral effects observed after exposure to commercial PCB mixtures.
• The findings support the utility of NEQs for assessing risks associated with PCB exposure.