Histone deacetylase 4 promotes ubiquitin-dependent proteasomal degradation of Sp3 in SH-SY5Y cells treated with di(2-ethylhexyl)phthalate (DEHP), determining neuronal death
Abstract
Phthalates, phthalic acid esters, are widely used as plasticizers to produce polymeric materials in industrial production of plastics and daily consumable products. Animal studies have shown that di(2-ethylhexyl)phthalate (DEHP) may cause toxic effects in the rat brain. In the present study, chronic exposure to DEHP (0.1-100μM) caused dose-dependent cell death via the activation of caspase-3 in neuroblastoma cells. Intriguingly, this harmful effect was prevented by the pan-histone deacetylase (HDAC) inhibitor trichostatin A, by the class II HDAC inhibitor MC-1568, but not by the class I HDAC inhibitor MS-275. Furthermore, DEHP reduced specificity protein 3 (Sp3) gene expression, but not Sp3 mRNA, after 24 and 48h exposures. However, Sp3 protein reduction was prevented by pre-treatment with MC-1568, suggesting the involvement of class II HDACs in causing this effect. Then, we investigated the possible relationship between DEHP-induced neuronal death and the post-translational mechanisms responsible for the down-regulation of Sp3. Interestingly, DEHP-induced Sp3 reduction was associated to its deacetylation and polyubiquitination. Co-immunoprecipitation studies showed that Sp3 physically interacted with HDAC4 after DEHP exposure, while HDAC4 inhibition by antisense oligodeoxynucleotide reverted the DEHP-induced degradation of Sp3. Notably, Sp3 overexpression was able to counteract the detrimental effect induced by DEHP. Taken together, these results suggest that DEHP exerts its…
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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 Guida et al., 2014
Additional evidence suggests broader dysregulation of the epigenetic machinery by phthalates, including altered expression of histone deacetylases such as HDAC4 and HDAC5.
“Additional evidence suggests broader dysregulation of the epigenetic machinery by phthalates, including altered expression of histone deacetylases such as HDAC4 and HDAC5, supporting the view that chromatin remodeling is a central component of their neurotoxic action (Guida et al., 2014).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Guida et al., 2014
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Ma, H., Xiao, J., Liu, J., Ma, M., Shao, X., Yan, X., Lai, J., & Li, X. (2026) · Environment International · doi:10.1016/j.envint.2026.110254
Baeblich, M., Bothe, M. K., & Klopfleisch, R. (2026) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2026.106225
- Authors
- Guida, N., Laudati, G., Galgani, M., Santopaolo, M., Montuori, P., Triassi, M., Di Renzo, G., Canzoniero, L. M. T., & Formisano, L.
- Affiliations
- University of Naples Federico II (IT)
- Institute for Experimental Endocrinology and Oncology (IT)
- University of Sannio (IT)
- Corresponding author
- Canzoniero, Lorella M.T.
- Formisano, Luigi
- ORCID
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 280
- Issue
- 1
- Pages
- 190-198
- ISSN
- 0041-008X (ISSN-L)
- OpenAlex
- W2087802053
- Cited by
- 46
- References
- 45
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 3 · 2015: 8 · 2014: 2
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- DEHP, phthalate toxicity, HDAC4, Sp3, ubiquitin-proteasome degradation, polyubiquitination, protein deacetylation, class II histone deacetylases, trichostatin A, entinostat, caspase-3 activation, neuronal cell death, neuroblastoma cells, SH-SY5Y cells
- MeSH terms
- Animals, Cell Survival, Diethylhexyl Phthalate, Dose-Response Relationship, Drug, Histone Deacetylases, Humans, Repressor Proteins, Cell Death, Rats, Wistar, Ubiquitin, Cell Line, Tumor, Proteasome Endopeptidase Complex, Rats, Histone Deacetylase Inhibitors
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