MiR-93 alleviates DEHP plasticizer-induced neurotoxicity by negatively regulating TNFAIP1 and inhibiting ubiquitin-mediated degradation of CK2β
Abstract
Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is widely used in various products, such as plastic packaging in food industries. As an environmental endocrine disruptor, it induces adverse effects on brain development and function. However, the molecular mechanisms by which DEHP induces learning and memory impairment remain poorly understood. Herein, we found that DEHP impaired learning and memory in pubertal C57BL/6 mice, decreased the number of neurons, downregulated miR-93 and the β subunit of casein kinase 2 (CK2β), upregulated tumor necrosis factor-induced protein 1 (TNFAIP1), and inhibited Akt/CREB pathway in mouse hippocampi. Co-immunoprecipitation and western blotting assays revealed that TNFAIP1 interacted with CK2β and promoted its degradation by ubiquitination. Bioinformatics analysis showed a miR-93 binding site in the 3'-untranslated region of Tnfaip1. A dual-luciferase reporter assay revealed that miR-93 targeted TNFAIP1 and negatively regulated its expression. MiR-93 overexpression prevented DEHP-induced neurotoxicity by downregulating TNFAIP1 and then activating CK2/Akt/CREB pathway. These data indicate that DEHP upregulates TNFAIP1 expression by downregulating miR-93, thus promoting ubiquitin-mediated degradation of CK2β, subsequently inhibiting Akt/CREB pathway, and finally inducing learning and memory impairment. Therefore, miR-93 can relieve DEHP-induced neurotoxicity and may be used as a potential molecular target for prevention and treatment of…
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Postnatal exposure to DEHP induces sex-specific changes in hippocampal microRNA expression.
“Postnatal exposure to DEHP has been shown to induce sex-specific changes in hippocampal microRNA expression.”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Qiu et al., 2023
Phthalates alter histone deacetylase expression and microRNA profiles, indicating disruption of neurodevelopmental programming at multiple regulatory levels.
“They alter histone deacetylase expression and microRNA profiles, indicating disruption of neurodevelopmental programming at multiple regulatory levels.”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Qiu et al., 2023
Downregulation of miR-93 together with upregulation of TNFAIP1 promotes degradation of protein kinase CK2β, leading to inhibition of the Akt/CREB signaling pathway and neuronal cell death.
“In particular, downregulation of miR-93 together with upregulation of TNFAIP1 promotes degradation of protein kinase CK2β, leading to inhibition of the Akt/CREB signaling pathway and ultimately neuronal cell death.”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Qiu et al., 2023
Epigenetically mediated alterations converge directly on key intracellular pathways involved in synaptic plasticity and neuronal survival.
“These epigenetically mediated alterations converge directly on key intracellular pathways involved in synaptic plasticity and neuronal survival (López-Merino et al., 2022; Qiu et al., 2023).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Qiu et al., 2023
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Childhood resolution of early abnormal miRNA following neonatal encephalopathy
Isaza-Correa, J. M., Isweisi, E., Murphy, R., Hurley, T., McGovern, M., O’Reilly, M., Tamgumus, S., King, G., O’Dea, M. I., Kelly, L. A., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-13776-9
El-Sheikh, S. M. A., Eleiwa, N. Z. H., Galal, A. A. A., Makled, A. E., & Abd‐Elhakim, Y. M. (2026) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/s44411-026-00799-5
- Authors
- Qiu, F., He, S., Zhang, Z., Dai, S., Wang, J., Liu, N., Li, Z., Hu, X., Xiang, S., & Wei, C.
- Affiliations
- Hunan Normal University (CN)
- Corresponding author
- Wei, Chenxi
- Venue
- Food and Chemical Toxicology
- Publisher
- Elsevier BV
- Published
- 2023-08
- Volume
- 178
- Pages
- 113888
- ISSN
- 0278-6915 (ISSN-L)
- OpenAlex
- W4380153988
- Cited by
- 16
- References
- 86
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 1 · 2023: 2
- FWCI
- 1.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Food and Chemical Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Hunan Province (2018JJ3330)
- National Natural Science Foundation of China (21806036, 81972642)
- Hunan Normal University
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- miR-93, DEHP, TNFAIP1, CK2β, ubiquitin-mediated proteolysis, learning and memory impairment, hippocampus, endocrine disruptors, microRNA target regulation, 3' untranslated region
- MeSH terms
- Animals, Carrier Proteins, Diethylhexyl Phthalate, Mice, Inbred C57BL, Plasticizers, Transcription Factors, Ubiquitin, MicroRNAs, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Mice
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