Inhibition of aldehyde detoxification in CNS mitochondria by fungicides

Among the several converging factors leading to Parkinson's disease, epidemiological studies indicate a correlation between Parkinson's disease (PD) with living in a rural area and/or exposure to agricultural pesticides. In this present study, we examined the potential of multiple agricultural pesticides for their ability to inhibit the function of whole, respiring rat brain mitochondria using the oxidation of the neurotoxic lipid-aldehyde trans-4-hydroxy-2-nonenal (HNE) as a biomarker for mitochondrial aldehyde dehydrogenase (ALDH) activity in situ. We chose an arbitrary cutoff concentration of 10 μM of each pesticide. Our data demonstrate that only four of the eighteen compounds tested inhibited oxidation of HNE to trans-4-hydroxy-2-nonenoic acid (HNEAcid). These compounds included rotenone, maneb, mancozeb, and benomyl. Surprisingly, maneb, mancozeb, and benomyl did not inhibit mitochondrial respiration but inhibited the activity of purified rat ALDH2 and rat ALDH5A, enzymes found in brain mitochondria that oxidize HNE and aldehydes derived from neurotransmitters. Our data demonstrate that mitochondrial ALDHs are sensitive targets of pesticide inactivation and that pesticides such as maneb and benomyl can decrease the detoxification of lipid peroxidation derived aldehydes such as HNE and, likely, aldehydes derived from neurotransmitters.