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Cited by 129Effects and risks of endocrine disrupting chemicalsToxic Organic Pollutants ImpactPesticide Exposure and Toxicity

Dibutyl phthalate (DBP)-induced apoptosis and neurotoxicity are mediated via the aryl hydrocarbon receptor (AhR) but not by estrogen receptor alpha (ERα), estrogen receptor Beta (ERβ), or peroxisome proliferator-activated receptor gamma (PPARγ) in mouse cortical neurons

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Wójtowicz, Anna K., Szychowski, Konrad A., Wnuk, Agnieszka, Kajta, Małgorzata·2017·Neurotoxicity Research
DOI 10.1007/s12640-016-9665-xPMC PMC5209414
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Abstract

Dibutyl phthalate (di-n-butyl phthalate, DBP) is one of the most commonly used phthalate esters. DBP is widely used as a plasticizer in a variety of household industries and consumer products. Because phthalates are not chemically bound to products, they can easily leak out to enter the environment. DBP can pass through the placental and blood-brain barriers due to its chemical structure, but little is known about its mechanism of action in neuronal cells. This study demonstrated the toxic and apoptotic effects of DBP in mouse neocortical neurons in primary cultures. DBP stimulated caspase-3 and LDH activities as well as ROS formation in a concentration (10 nM-100 µM) and time-dependent (3-48 h) manner. DBP induced ROS formation at nanomolar concentrations, while it activated caspase-3 and LDH activities at micromolar concentrations. The biochemical effects of DBP were accompanied by decreased cell viability and induction of apoptotic bodies. Exposure to DBP reduced Erα and Pparγ mRNA expression levels, which were inversely correlated with protein expression of the receptors. Treatment with DBP enhanced Ahr mRNA expression, which was reflected by the increased AhR protein level observed at 3 h after exposure. ERα, ERβ, and PPARγ antagonists stimulated DBP-induced caspase-3 and LDH activities. AhR silencing demonstrated that DBP-induced apoptosis and neurotoxicity are mediated by AhR, which is consistent with the results from DBP-induced enhancement of AhR mRNA and protein expression. Our study showed that AhR is involved in DBP-induced apoptosis and neurotoxicity, while the ERs and PPARγ signaling pathways are impaired by the phthalate.

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  • DBP and related compounds are antiandrogenic but also interact with PPARγ and AhR, thereby affecting transcriptional regulation, apoptosis, and neurodevelopmental programming.

    “DBP and related compounds are best known for their antiandrogenic activity, but they also interact with peroxisome proliferator-activated receptors, particularly peroxisome proliferator-activated receptor gamma (PPARγ), and with the aryl hydrocarbon receptor (AhR), thereby affecting transcriptional regulation, apoptosis, and neurodevelopmental programming (Kajta et al., 2009; Wójtowicz et al., 201”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Wójtowicz et al., 2017

    The Introduction says DBP can bind PPARγ and AhR, and the Discussion describes DBP as an androgen-receptor antagonist. The Results report changes in receptor mRNA expression, while the Discussion links DBP-induced apoptosis and neurotoxicity in mouse cortical neurons to AhR, not PPARγ. The paper does not establish neurodevelopmental programming effects or the same effects for related compounds. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Wójtowicz, A. K., Szychowski, K. A., Wnuk, A., & Kajta, M.
Affiliations
  • University of Agriculture in Krakow (PL)
  • University of Information Technology and Management in Rzeszow (PL)
  • Maj Institute of Pharmacology (PL)
Corresponding author
Wójtowicz, Anna K.
ORCID
Venue
Neurotoxicity Research
Publisher
Springer Science and Business Media LLC
Published
2016-08-31
Volume
31
Issue
1
Pages
77-89
ISSN
  • 1029-8428 (ISSN-L)
  • 1476-3524
DOI
10.1007/s12640-016-9665-x
PMC
PMC5209414
OpenAlex
W2517795426
Cited by
129
References
1
Citations by year
2026: 14 · 2025: 12 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 19 · 2020: 14 · 2019: 9 · 2018: 11 · 2017: 11 · 2016: 1
FWCI
6.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurotoxicity Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Polish National Science Centre (2012/07/B/NZ4/00238)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
Keywords
dibutyl phthalate, phthalates, neurotoxicity, apoptosis, aryl hydrocarbon receptor, estrogen receptor alpha, estrogen receptor beta, PPARγ, caspase-3, reactive oxygen species, cortical neurons, receptor antagonists, plasticizers
MeSH terms
Animals, Cell Survival, Cells, Cultured, Cerebral Cortex, Dibutyl Phthalate, Dose-Response Relationship, Drug, Neurons, RNA, Messenger, Time Factors, Apoptosis, Reactive Oxygen Species, Receptors, Aryl Hydrocarbon, PPAR gamma, Estrogen Receptor alpha, Estrogen Receptor beta, Mice, Caspase 3

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