Benzyl butyl phthalate exposure impairs learning and memory and attenuates neurotransmission and CREB phosphorylation in mice
Abstract
The existing data are insufficient to evaluate the neurotoxicity of benzyl butyl phthalate (BBP) exposure on the brain, and the underlying mechanisms to explain these effects remain unclear. Kun Ming (KM) mice were exposed to BBP (0, 50, 250, 1250 mg/kg) via gavage for 14 days. Employing the Morris water maze (MWM) test, we observed that mice demonstrated poorer learning and memory performance than the control group at doses of 250 and 1250 mg/kg/day. Reduction of locomotor activity in mice and depression were indicated by a long "dead time" in the Forced Swim Test and tail suspension test. Pathological alterations and oxidative damage to the hippocampus were found. To study the molecular mechanisms underlying BBP toxicity, the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) and pCREB were tested. The modified levels of 5-HT in the hippocampus and the decreased levels of CREB phosphorylation after BBP exposure suggested a potential mechanism underlying BBP toxicity. We hypothesize that BBP exposure causes a decrease in the number of neurotransmitters, which in turn down regulates the levels of CREB phosphorylation by the cAMP/protein kinase A (PKA)-mediated signaling. The results are an attenuation of the effects of CREB downstream, oxidative damage and impaired behavioral performance.
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Chronic exposure alters expression of plasticity-associated proteins including ERK1/2, MeCP2, and ERα.
“Chronic exposure also alters the expression of plasticity-associated proteins, including ERK1/2, MeCP2, and ERα (Betz et al., 2013; Min et al., 2014).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Min et al., 2014
BBP reduces activity of the transcription factor CREB, a central regulator of LTP, LTD, and memory formation.
“BBP has been shown to reduce the activity of the transcription factor CREB, a central regulator of LTP, LTD, and memory formation.”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Min et al., 2014
Cites
The tail suspension test: A new method for screening antidepressants in mice
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Phthalates and other additives in plastics: human exposure and associated health outcomes
Meeker, J. D., Sathyanarayana, S., & Swan, S. H. (2009) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2008.0268 · Cited by 835 · see citing works
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Seralini, G.-E., & Jungers, G. (2021) · Toxicology Reports · doi:10.1016/j.toxrep.2021.07.014 · Cited by 57 · see citing works
Jocsak, G., Kiss, D. S., Alymbaeva, D., Diebald, A., Zsarnovszky, A., Heinzlmann, A., & Bartha, T. (2026) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2026.1821381 · Cited by 1 · see citing works
“Chronic exposure also alters the expression of plasticity-associated proteins, including ERK1/2, MeCP2, and ER α (Betz et al., 2013; Min et al., 2014).”
- Authors
- Min, A., Liu, F., Yang, X., & Chen, M.
- Affiliations
- Central China Normal University (CN)
- Corresponding author
- Chen, Mingqing
- Venue
- Food and Chemical Toxicology
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 71
- Pages
- 81-89
- ISSN
- 0278-6915 (ISSN-L)
- OpenAlex
- W2060982382
- Cited by
- 45
- References
- 2
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 3
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Food and Chemical Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation of China (51136002)
- National Key Technologies R&D Program of China (2012BAJ02B03)
- 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
- butyl benzyl phthalate, learning and memory impairment, CREB phosphorylation, serotonin, locomotor activity, depression-like behavior, cAMP/PKA signaling, behavioral toxicity
- MeSH terms
- Animals, Glutathione, Memory, Phosphorylation, Phthalic Acids, Serotonin, Lipid Peroxidation, Cyclic AMP Response Element-Binding Protein, Reactive Oxygen Species, Maze Learning, Mice
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