Biology subjects

Ilieva, N. M.

Publications and source records attributed to Ilieva, N. M..

3 recordsLinked to original sources

bioRxiv2026

Metabolism of trichloroethylene following inhalation exposure in mice

Trichloroethylene (TCE) is a pervasive environmental pollutant associated with elevated risk of developing Parkinson's disease (PD). Studies characterizing TCE metabolism in humans indicate that 40 - 75% of the absorbed dose is metabolized, suggesting that TCE toxicity may be attributable to its metabolites. However, there is limited knowledge of TCE metabolite neurotoxicity. We conducted a TCE inhalation study in mice followed by high-resolution mass spectrometry (HRMS) on brain, liver, and blood to identify which TCE metabolites were present following human-relevant TCE exposure. Mice were exposed to 100 ppm TCE for 4 hours. Plasma, brain, and liver were collected from each animal up to 24 hours after exposure. We developed a method capable of detecting TCE metabolites trichloroacetic acid (TCA), dichloroacetic acid (DCA), monochloroacetic acid (MCA), trichloroethanol (TCEOH), trichloroethanol glucuronide (TCEOH-gluc), S-(1,2-dichlorovinyl)glutathione (DCVG), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC), and untargeted metabolites using a single extraction protocol on a liquid chromatography-based mass spectrometry system (LC-MS/MS). Targeted analysis of TCE-exposed biological samples identified DCA, TCA, and TCEOH-gluc. Untargeted analysis of TCE-exposed mouse brain revealed previously established and novel pathway perturbations associated with TCE exposure. Together, these findings indicate that DCA, TCA, and TCEOH-gluc are the most prevalent TCE metabolites in mice. The novel pathways perturbed by TCE exposure warrant further exploration to better understand the mechanisms underlying the toxicity of TCE and its metabolites

pharmacology and toxicology↗

bioRxiv2024

LRRK2 kinase inhibition protects against Parkinson's disease-associated environmental toxicants

Idiopathic Parkinsons disease (PD) is epidemiologically linked with exposure to toxicants such as pesticides and solvents, which comprise a wide array of chemicals that pollute our environment. While most are structurally distinct, a common cellular target for their toxicity is mitochondrial dysfunction, a key pathological trigger involved in the selective vulnerability of dopaminergic neurons. We and others have shown that environmental mitochondrial toxicants such as the pesticides rotenone and paraquat, and the organic solvent trichloroethylene (TCE) appear to be influenced by the protein LRRK2, a genetic risk factor for PD. As LRRK2 mediates vesicular trafficking and influences endolysosomal function, we postulated that LRRK2 kinase activity may inhibit the autophagic removal of toxicant damaged mitochondria, resulting in elevated oxidative stress. Conversely, we suspected that inhibition of LRRK2, which has been shown to be protective against dopaminergic neurodegeneration caused by mitochondrial toxicants, would reduce the intracellular production of reactive oxygen species (ROS) and prevent mitochondrial toxicity from inducing cell death. To do this, we tested in vitro if genetic or pharmacologic inhibition of LRRK2 (MLi2) protected against ROS caused by four toxicants associated with PD risk - rotenone, paraquat, TCE, and tetrachloroethylene (PERC). In parallel, we assessed if LRRK2 inhibition with MLi2 could protect against TCE-induced toxicity in vivo, in a follow up study from our observation that TCE elevated LRRK2 kinase activity in the nigrostriatal tract of rats prior to dopaminergic neurodegeneration. We found that LRRK2 inhibition blocked toxicant-induced ROS and promoted mitophagy in vitro, and protected against dopaminergic neurodegeneration, neuroinflammation, and mitochondrial damage caused by TCE in vivo. We also found that cells with the LRRK2 G2019S mutation displayed exacerbated levels of toxicant induced ROS, but this was ameliorated by LRRK2 inhibition with MLi2. Collectively, these data support a role for LRRK2 in toxicant-induced mitochondrial dysfunction linked to PD risk through oxidative stress and the autophagic removal of damaged mitochondria.

neuroscience↗

bioRxiv2022

Oral ingestion of the environmental toxicant trichlorethylene in rats induces alterations in the gut microbiome: relevance to idiopathic Parkinson's disease

Microbial alterations within the gut microbiome appear to be a common feature of individuals with Parkinsons disease (PD), providing further evidence for the role of the gut-brain axis in PD development. As a major site of contact with the environment, questions have emerged surrounding the cause and effect of alterations to the gut microbiome by environmental contaminants associated with PD risk, such as pesticides, metals, and organic solvents. Recent data from our lab shows that ingestion of the industrial byproduct and environmental pollutant trichloroethylene (TCE) induces key Parkinsonian pathology within aged rats, including the degeneration of dopaminergic neurons, -synuclein accumulation, neuroinflammation, and endolysosomal deficits. As TCE is the most common organic contaminant within drinking water, we postulated that ingestion of TCE associated with PD-related neurodegeneration may alter the gut microbiome to a similar extent as observed in persons with PD. To assess this, we collected fecal samples from adult rats treated with 200 mg/kg TCE over 6 weeks via oral gavage - the dose that produced nigrostriatal neurodegeneration - and analyzed the gut microbiome via whole genome shotgun sequencing. Our results showed changes in gut microorganisms reflective of the microbial signatures observed in individuals with idiopathic PD, such as decreased abundance of short-chain fatty acid producing Blautia and elevated lactic-acid producing Bifidobacteria, as well as genera who contain species previously reported as opportunistic pathogens such as Clostridium. From these experimental data, we postulate that TCE exposure within contaminated drinking water could induce alterations of the gut microbiome that contributes to chronic disease risk, including idiopathic PD.

pharmacology and toxicology↗