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Real-world neonicotinoid mixture exposure reveals synergistic cytotoxicity and divergent pathway vulnerabilities in human cell lines

ABSTRACT:

In this study, five human cell lines (A2780, Chang liver, HEK293T, HeLa, and HepG2) were used as models and exposed to mixtures of neonicotinoids (NEOs) and their metabolites. The mixture concentrations were prepared based on human biomonitoring data to reflect the actual detected levels of NEOs and their metabolites in human urine. Each cell line was treated with the corresponding human biomonitoring-matched mixture at specified concentrations, alongside a 0.1% DMSO solvent control group. After 48 hours of exposure, intracellular metabolites were extracted and subjected to untargeted metabolomic analysis using an Orbitrap Exploris 120 mass spectrometer in both positive and negative ion modes. During the acquisition process, pooled quality control samples (prepared by mixing equal volumes of all samples) were interspersed to monitor system stability.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS13896 | MetaboLights | 2026-06-22

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13896_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13896_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13896_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13896_LC-MS_positive_hilic_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Marine biomonitoring programs in the U.S. and Europe have historically relied on monitoring tissue concentrations of bivalves to monitor contaminant levels and ecosystem health. By integrating ‘omic methods with these tissue residue approaches we can uncover mechanistic insight to help link tissue concentrations to toxic effects. In an effort to identify novel biomarkers and better understand the molecular toxicology of metal bioaccumulation in bivalves, we exposed the blue mussel, Mytilus edulis L., to sub-lethal concentrations (0.54 M) of cadmium, lead, and a Cd+Pb mixture. Metal concentrations were measured in gill tissues at 1, 2, and 4 weeks, and increased linearly over the 4 week duration. In addition, there was evidence that Pb interfered with Cd uptake in the mixture treatment. Using a 3025 sequence microarray for M. edulis, we performed transcriptomic analysis, identifying 57 differentially expressed sequences. Hierarchical clustering of these sequences successfully distinguished the different treatment groups demonstrating that the expression profiles were reproducible among the treatments. Enrichment analysis of gene ontology terms identified several biological processes that were perturbed by the treatments, including nucleoside phosphate biosynthetic processes, mRNA metabolic processes, and response to stress. To identify transcripts whose expression level correlated with metal bioaccumulation, we performed Pearson correlation analysis. Several transcripts correlated with gill metal concentrations including mt10, mt20, and contig 48, an unknown transcript containing a wsc domain. In addition, three transcripts directly involved in the Unfolded protein response (UPR) were induced in the metal treatments at 2 weeks and were further up-regulated at 4 weeks. Overall, correlation of tissue concentrations and gene expression responses indicates that as mussels accumulate higher concentrations of metals, initial stress responses are mobilized to protect tissues. However, given the role of UPR in apoptosis, it serves as an early indicator of stress, which once overwhelmed will result in adverse physiological effects.

Project description:Marine biomonitoring programs in the U.S. and Europe have historically relied on monitoring tissue concentrations of bivalves to monitor contaminant levels and ecosystem health. By integrating M-bM-^@M-^Xomic methods with these tissue residue approaches we can uncover mechanistic insight to help link tissue concentrations to toxic effects. In an effort to identify novel biomarkers and better understand the molecular toxicology of metal bioaccumulation in bivalves, we exposed the blue mussel, Mytilus edulis L., to sub-lethal concentrations (0.54 M-oM-^AM--M) of cadmium, lead, and a Cd+Pb mixture. Metal concentrations were measured in gill tissues at 1, 2, and 4 weeks, and increased linearly over the 4 week duration. In addition, there was evidence that Pb interfered with Cd uptake in the mixture treatment. Using a 3025 sequence microarray for M. edulis, we performed transcriptomic analysis, identifying 57 differentially expressed sequences. Hierarchical clustering of these sequences successfully distinguished the different treatment groups demonstrating that the expression profiles were reproducible among the treatments. Enrichment analysis of gene ontology terms identified several biological processes that were perturbed by the treatments, including nucleoside phosphate biosynthetic processes, mRNA metabolic processes, and response to stress. To identify transcripts whose expression level correlated with metal bioaccumulation, we performed Pearson correlation analysis. Several transcripts correlated with gill metal concentrations including mt10, mt20, and contig 48, an unknown transcript containing a wsc domain. In addition, three transcripts directly involved in the Unfolded protein response (UPR) were induced in the metal treatments at 2 weeks and were further up-regulated at 4 weeks. Overall, correlation of tissue concentrations and gene expression responses indicates that as mussels accumulate higher concentrations of metals, initial stress responses are mobilized to protect tissues. However, given the role of UPR in apoptosis, it serves as an early indicator of stress, which once overwhelmed will result in adverse physiological effects. A total of 52 samples including initial samples and 3 time-points following exposure to cadmium, lead, or a mixture. There were four replicate samples for each treatment and time-point. An additional three replicate samples were used for RT-qPCR.

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Real-world neonicotinoid mixture exposure reveals synergistic cytotoxicity and divergent pathway vulnerabilities in human cell lines

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