Cross-species metabolomic analysis of tau- and DDT-related toxicity

Abstract

Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of Alzheimer's disease (AD), a disease also associated with hyperphosphorylated tau (p-tau) protein aggregation. We investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans using a transgenic strain that expresses human tau protein prone to aggregation by measuring changes in size, swim behavior, respiration, lifespan, learning, and metabolism. In addition, we examined the association between cerebrospinal fluid (CSF) p-tau protein – as a marker of post-mortem tau burden – and global metabolism in both a human population study and in C. elegans, using the same p-tau transgenic strain. From the human population study, plasma and CSF-derived metabolic features associated with p-tau levels were related to drug, amino acid, fatty acid and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of p-tau protein on growth and basal respiration. In the presence of p-tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Our findings in C. elegans indicate that DDT exposure and p-tau aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of p-tau aggregation. Further, biological pathways associated with exposure to DDT and the pathogenic Alzheimer's protein appear to be conserved between species.

Effect of pesticides on phosphorylation of tau protein, and its influence on Alzheimer’s disease

“…Increased oxidative stress over-activates GSK-3β, thereby making tau protein more vulnerable to formation of aggregates and new neurofibrils[ 41 ]. Results from multiple studies indicate that exposure to pesticides modifies the mechanisms involved in tau phosphorylation[ 32 - 34 , 42 , 43 ] (Figure 1 ).…”

“…Table 1 shows 7 studies in which the effect of OCs on tau protein phosphorylation was determined[ 42 , 44 - 49 ]. Two clinical studies reported that exposure to these pesticides may be associated with polymorphisms in MAPT and microtubule associated protein 1B gene which are related to the formation of tau aggregates[ 44 , 45 ].…”

“…Two clinical studies reported that exposure to these pesticides may be associated with polymorphisms in MAPT and microtubule associated protein 1B gene which are related to the formation of tau aggregates[ 44 , 45 ]. Studies have demonstrated that dichlorodiphenyltrichloroethan exposure to an OC altered mitochondrial function, resulting in the formation of tau aggregates, with up-regulations in the expressions of proteins such as synaptosome-associated protein 25 kDa, cytochrome C, enolase A, hemoglobin alpha chain and histone cluster 1, which are characteristic of AD[ 42 , 46 , 47 ]. Finally, Mir et al [ 48 ] has shown that exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin induced overexpression of GSK-3β, and hence tau phosphorylation.…”

“…Finally, Mir et al [ 48 ] has shown that exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin induced overexpression of GSK-3β, and hence tau phosphorylation. In all, 4 of the 7 studies described in Table 1 reported increases in tau phosphorylation[ 42 , 44 , 46 , 48 ]. Therefore, OCs have been associated with development of tauopathy which leads to axonal instability, mitochondrial dysfunction and neuroinflammation[ 44 ].…”

The worm Adult Activity Test (wAAT): A de novo mathematical model for detecting acute chemical effects in Caenorhabditis elegans

“…While the C. elegans simple body plan lacks multiple organs present in mammals, many aspects of neuronal development and function are conserved from worms to humans (Bargmann, 1998; Boyd et al, 2010; Vidal‐Gadea & Pierce‐Shimomura, 2012). Mammalian neurotoxins have been shown to alter C. elegans locomotor activity levels and/or behavior patterns (Cole et al, 2004; Gentry et al, 2013; Ju et al, 2014; Kalia et al, 2022; Silva, 2020; Williams & Dusenbery, 1990). Additionally, C. elegans has a high true prediction rate with respect to the effects of human neurotoxicants on behavior (Masjosthusmann et al, 2018).…”