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. 2025 Aug 29;4(1):54–64. doi: 10.1021/envhealth.5c00171

Developmental Mono(2-ethylhexyl) Phthalate Exposure Impairs Offspring Neurobehavior through Suppression of CYP450 Transcriptional Pathways

Jingcun Dong †,∥, Jia Yin ⊥, Shuang Liu †,‡, Qingqing Zhu †,∥, Jiaying Liu #, Jinfeng Peng 7, Chunyang Liao †,‡,§,∥,*, Guibin Jiang †,‡,∥
PMCID: PMC12813708  PMID: 41562039

Abstract

Phthalates, ubiquitous environmental contaminants, pose substantial risks to neurodevelopment, yet the mechanisms underlying their toxicity remain largely unknown. This study demonstrates that developmental exposure to mono­(2-ethylhexyl) phthalate (MEHP: 0, 10, and 50 mg/kg), the bioactive metabolite of di­(2-ethylhexyl) phthalate (DEHP), induced neurobehavioral deficits in adolescent offspring rats. Behavioral assessments revealed that the MEHP exposure provoked anxiety-like behaviors at postnatal days (PND) 14 and 21, concurrently manifested as spatial memory impairments at PND35. Histopathological analysis demonstrated significant neurodegenerative alterations in the hippocampus of MEHP-exposed offspring, including reduced Nissl body density in the 50 mg/kg group. Transcriptomic profiling identified a robust dose-dependent dysregulation pattern, with high-dose exposure (50 mg/kg) eliciting substantially more differentially expressed genes (542 DEGs) than low-dose exposure (393 DEGs). Analysis revealed suppression of cytochrome P450 (CYP450) pathways, characterized by the downregulation of Cyp2a1, Cyp2f4, Cyp2g1, and Cyp1a2. Strikingly, these effects occurred independently of canonical xenobiotic-sensing receptors, indicating direct CYP450 transcriptional inhibition as a potential novel mechanism. Taken together, our findings determine MEHP as a potent developmental neurotoxicant, with CYP450 dysregulation identified as a critical mediator of phthalate-induced neurotoxicity, with significant implications for environmental risk assessment.

Keywords: Mono(2-ethylhexyl) phthalate, Exposure, Neurotoxicity, RNA-Seq, CYP450 dysregulation

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1. Introduction

Phthalic acid esters (PAEs), commonly known as phthalates, are a class of chemical plasticizers widely used in polymer production. They serve as plasticizers and solvents in diverse products, including medical devices (e.g., infusion tubes), food packaging materials, toys, and personal care products (e.g., cosmetics). − Due to their weak and noncovalent bonds with plastic matrices, PAEs are prone to leaching through volatilization, migration, and leaching, resulting in ubiquitous human exposure via dietary intake, inhalation, and dermal contact. , PAEs and their metabolites have been detected in >90% of human biological samples, including urine, serum, and breast milk. ,− Both low- and high-molecular-weight PAEs (e.g., Diethyl phthalate, Dibutyl phthalate; DEHP, Diisononyl phthalate) raise significant concerns due to their widespread environmental occurrences and potential health risks. ,− Among PAEs, DEHP and its metabolites (e.g., MEHP, Mono­(2-ethylhexyl) hydroxyphthalate, Mono­(2-ethylhexyl) oxoaphthalate) are notable for their high environmental persistence and toxicity. − In vivo, DEHP is rapidly metabolized by intestinal enzymes into its primary bioactive metabolite, MEHP which exhibits substantially greater toxicity than the parent compound (i.e., DEHP). − Current research on DEHP and MEHP primarily focuses on hepatotoxicity, nephrotoxicity, reproductive toxicity, − cardiovascular toxicity, , and thyroid toxicity, ,, however, their neurotoxicity remains largely unknown.

PAEs, particularly DEHP, can induce adverse health effects during critical neurodevelopmental periods, including the fetal and early postnatal stages. These compounds can traverse the placental barrier, blood-brain barrier, and gut-brain axis, accumulating in the central nervous system. ,− Epidemiological studies have revealed an inverse correlation between prenatal maternal urinary concentrations of specific DEHP metabolites (including MEHP) in mother and psychomotor development indices in infants. , In school-aged children and adolescents, elevated urinary DEHP metabolite levels have been associated with increased incidence of attention-deficit/hyperactivity disorder, learning disabilities, and social behavioral impairments. , Children diagnosed with autism spectrum disorder exhibit considerably higher urine and serum concentrations of DEHP, MEHP, and other phthalates compared to healthy controls. − Animal studies demonstrate that perinatal or adolescent exposure to DEHP impairs cognitive function, social behavior, and spatial learning in rodent offspring. − Behavioral assessments, including the elevated plus maze (EPM) test, novel object recognition test, and forced swim test, have shown that DEHP exposure induced anxiety- and depression-like behaviors in offspring generations. − Additionally, DEHP disrupts mating behavior, shortening copulatory duration and compromising reproductive success in animal models. , However, the molecular mechanisms underlying DEHP-induced neurodevelopmental disruption, neural dysfunction, and pathogenesis of neurodevelopmental disorders remain poorly characterized, particularly for its highly toxic primary metabolite, MEHP.

Understanding the neurotoxic effects and associated mechanisms of MEHP is critical for comprehensive risk assessment of DEHP. In this study, pregnant Sprague–Dawley (SD) rats were used to investigate the neurotoxicity of MEHP on offspring and elucidate the underlying molecular mechanisms. The neurotoxic effects of MEHP on offspring were assessed through the morphological analysis, immunofluorescence-based quantification of synaptic protein markers, and behavioral testing. Furthermore, differential transcriptome sequencing and bioinformatics analysis were conducted to identify dysregulated pathways and signaling molecules mediating MEHP-induced neurotoxicity. These findings aim to provide direct experimental evidence for MEHP neurotoxicity, thereby enhancing the mechanistic understanding of its health risks.

2. Materials and Methods

Pregnant SD rats on gestational day (GD) 14.5 were obtained from SPF Biotechnology Co., Ltd. (Beijing, China) for this study. Dams were randomly assigned to three groups (n = 5 per group) and administered daily oral gavages of corn oil (control), 10 mg/kg MEHP (low dose), or 50 mg/kg MEHP (high dose) from GD14 to PND21. Offspring (n = 120) were exposed through placental transfer and maternal lactation. The low-dose exposure was selected to reflect estimated human exposure levels from dietary/environmental assessments, whereas the high dose exposure was chosen to represent high-risk exposure scenarios. ,, All procedures were approved by the Institutional Animal Care and Use Committee of the Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences (AEWC-RCEES-2021052) and were conducted in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals (NIH, 2011).

Offspring were standardized to 8 pups (4 males and 4 females) at birth and weaned at PND21. Throughout the exposure period, no mortality occurred in dams or offspring across all groups including the controls. Prior to behavioral testing, all offspring underwent neurological screening using a standardized observational battery, with no gross neurological impairments detected. Behavioral evaluations included the EPM (PND14), Open Field Test (OFT, PND21), and Morris Water Maze (MWM, PND35) to assess anxiety-like behavior, locomotor activity, and cognitive function. Upon completion of behavioral testing, offspring were euthanized for brain tissue collection (PND 35). Hippocampal tissues were processed for histopathological analysis (hematoxylin-eosin (H&E) and Nissl staining) and molecular analysis (immunohistochemistry, RNA sequencing, and quantitative reverse transcription PCR (RT-qPCR)). Comprehensive methodological details are available in the Supporting Information (Texts S1–S6). Data are presented as mean ± standard error of the mean (SEM). Statistical analyses were performed using one-way or two-way analysis of variance (ANOVA) with Dunnett’s post-hoc test implemented in SPSS 19.0 (IBM Corp.) and R (v4.0.2; R Foundation). Statistical significance threshold was established at p < 0.05.

3. Results

3.1. MEHP Exposure Induces Anxiety-like Behaviors in Offspring

Behavioral assessments were performed to evaluate anxiety-related outcomes in offspring treated with MEHP. Representative movement trajectories from the EPM are illustrated in Figure A, showing diminished open-arm exploration in the high-dose MEHP-exposed offspring, characterized by reduced entries and restricted path coverage. Compared with the controls, decreased total movement distance (Figure B) was recorded in the high-dose MEHP group during the EPM testing. In the low-dose group, fewer entries into the open arms were observed (Figure C), while both MEHP-exposed groups exhibited shorter movement distances within the open arms (Figure D).

1.

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Behavioral analysis of EPM and OFT following the MEHP exposure. (A) Diagram of the movement trajectories of offspring rats. (B) Measurement of total distance traveled by offspring. (C) Recording the number of times the offspring entered the open arms. (D) Measurement of the distance moved by the offspring in the open arms. (E) Diagram of the movement trajectories of offspring rats. (F) Measurement of total distance traveled by offspring. (G) Recording the number of times the offspring entered the central region. (H) Measurement of the distance moved by the offspring in the central region.

In the OFT test (Figure E), no obvious differences in total movement distance were found between the MEHP-exposed and the control groups (Figure F). However, the high-dose group displayed fewer central zone entries and reduced central area distance (Figure G, H), indicating enhanced thigmotaxis (wall-hugging behavior). Collectively, these results demonstrate that the MEHP exposure induces anxiety-like behaviors in offspring.

3.2. MEHP Exposure Impairs Hippocampal-Dependent Spatial Learning and Memory Impairment in Offspring

Given the established association between hippocampal dysfunction and cognitive impairment, the MWM test was employed to evaluate spatial learning and memory functions. During the acquisition phase (Days 1–5), longer escape latencies were observed in the MEHP-exposed offspring (Figure B). On Day 6 probe trial, no considerable difference in target quadrant escape latency was found between the high-dose MEHP-exposed groups and the control group (Figure C). However, reduced average swimming speed were observed across all the MEHP-exposed groups (Figure F). Representative Day 6 swimming trajectories (Figure A) reveal diminished target quadrant exploration in the high-dose MEHP-exposed offspring, consistent with impaired spatial memory retention. During the probe trial, the high-dose MEHP-exposed offspring showed fewer platform crossings (within 90 s) (Figure E) and markedly reduced target quadrant dwell time (Figure D). These findings collectively demonstrate that the developmental MEHP exposure disrupts hippocampal-dependent learning and memory, with the high-dose exposure inducing more pronounced cognitive deficits.

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MWM cognitive assessment following the MEHP exposure. (A) Diagram of the movement trajectory of offspring rats. (B) Measurement of the time required for rats to move from the third quadrant to the target platform during the learning trial (Days 1–5). (C) Measurement of the time for the offspring to enter the target area for the first time on Day 6. (D) Record of the number of times the offspring entered the target area on Day 6. (E) Proportion of time spent in the target quadrant by offspring on Day 6. (F) Measurement of the average speed during the probe trial of Day 6 offspring.

3.3. MEHP Exposure Induces Hippocampal Neuronal Damage

Hippocampal neuron function is essential for cognitive learning and memory. In the present study, H&E staining was employed to assess neuronal morphology in hippocampal subregions (cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and dentate gyrus (DG)). As shown in Figure A, control-group neurons were characterized by typical pyramidal morphology, intact cytoarchitecture, well-defined nuclear membranes, and distinct nucleoli. In contrast, the MEHP-exposed groups exhibited marked histopathological alterations, including increased nucleolar basophilia, disorganized laminar architecture, and neurodegenerative pathologies such as nuclear pyknosis and focal necrotic lesions.

3.

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Histomorphological and neuronal analysis of hippocampal slices from offspring brains via H&E staining and Nissl staining. (A) H&E staining and Nissl staining were used to stain hippocampal CA1, CA3, and DG regions, respectively. Scale bars: 100 μm in the overview hippocampal neuronal sections across distinct regions and 50 μm in the magnified views of dashed-box regions. CA1: cornu ammonis 1, CA3: cornu ammonis 3, and DG: dentate gyrus. (B) Neuronal counting of hippocampal slices from the brains of offspring.

Subsequently, Nissl staining was performed to quantify Nissl body density across hippocampal subfields. As shown in Figure B, region-specific reductions were observed, with diminished Nissl body density being detected in the CA1 and CA3 subfields of MEHP-exposed rats, whereas no obvious changes were found in the DG region.

3.4. MEHP Exposure Alters Synaptogenesis-Related Protein Expression in Offspring

Dendritic spines, which are specialized components forming synaptic connections along neuronal dendrites, are essential for learning and memory. Quantitative immunohistochemical analysis of the hippocampal region in offspring (Figure ) revealed that developmental exposure to the high-dose MEHP (50 mg/kg) obviously downregulated the expression of postsynaptic density protein 95 (PSD-95) and myelin basic protein (MBP) compared with the age-matched controls. Conversely, no marked alterations were observed in synaptophysin (SYP) expression between the MEHP-exposed and control groups (Figure ).

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IHC staining and analysis of hippocampal slices from the brains of the offspring. Scale bars: 100 μm in the overview hippocampal neuronal sections across distinct regions, and 50 μm in the magnified views of dashed-box regions.

3.5. Mechanistic Insights into MEHP-Induced Neurotoxicity in Offspring

To elucidate the molecular mechanisms underlying anxiety and learning deficits caused by the gestational and lactational MEHP exposure, RNA sequencing (RNA-Seq) was conducted on PND 35 offspring brain tissues. The high-dose MEHP exposure elicited 542 DEGs (355 upregulated, 187 downregulated; Figure S1A), while the low-dose exposure induced 393 DEGs (293 upregulated, 100 downregulated; Figure S1B). The increased number of DEGs in the high-dose group was indicative of dose-dependent neurotoxic effects of MEHP, with toxicity being intensified at higher exposure levels. Through Venn diagram analysis, 101 overlapping DEGs were identified between the MEHP-exposed groups and controls, of which 96 were common to the high-dose and control groups, and 59 were shared between the low-dose and control groups. Subsequent analyses focused on the high-dose group (50 mg/kg) for enhanced detection sensitivity included differential expression, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, prioritizing targets for RT-qPCR validation.

GO enrichment analysis (FDR < 0.05) revealed significantly enriched terms in molecular functions including steroid hydroxylase and oxidoreductase activities and biological processes particularly CYP450 pathways and xenobiotic metabolism (Figure A). KEGG analysis identified key pathways mediating MEHP toxicity: CYP450-mediated xenobiotic metabolism, drug metabolism-CYP450, steroid hormone biosynthesis, and metabolic pathways (Figure B). These findings were validated by Gene Set Enrichment Analysis (Figure C). Substantial downregulation of CYP450 genes (Cyp2a1, Cyp2f4, Cyp2g1, and Cyp1a2) was confirmed by RT-qPCR in the MEHP-exposed offspring, while no obvious alteration in Ugt2a3 expression was found (Figure D).

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Potential molecular mechanisms were explored by RNA-Seq and bioinformatics analysis. (A) GO enrichment analysis. (B) KEGG enrichment analysis. (C) Gene Set Enrichment Analysis of the pathway in KEGG enrichment analysis. (D) Changes in CYP450-related mRNA expression in offspring after the MEHP exposure.

4. Discussion

In this study, evidence is provided that MEHP, the highly toxic metabolite of DEHP, induced adverse neurobehavioral outcomes in offspring rats. Hippocampal histomorphological damage was induced in the hippocampal region by the MEHP exposure, accompanied by impairment of neural transmission and disruption of early life spontaneous locomotor activity, as well as learning and memory capacities. Transcriptomic analysis identified obvious downregulation of CYP450-related genes (Cyp2a1, Cyp2f4, Cyp2g1, and Cyp1a2) following the MEHP exposure (Table S3). Our findings demonstrate that developmental MEHP exposure induces substantial neurobehavioral dysfunction, including anxiety-like behaviors and spatial memory deficits in adolescent offspring. This novel finding determines MEHP as a potent developmental neurotoxicant, identifies CYP450 dysregulation as the pivotal mediator of its neurotoxicity, and reveals prenatal/lactational development as a defining susceptibility window for phthalate-induced neurodevelopmental impairment.

MEHP, the primary metabolite of DEHP in biological systems, has been demonstrated to exhibit greater toxicity than its parent compound and considered to be the key contributor to DEHP-induced toxic effects. To date, few studies have examined the neurotoxic effects of MEHP and the relevant underlying molecular mechanisms. , Environmentally relevant MEHP concentrations induced neurotoxicity in zebrafish through oxidative stress, apoptosis, and acetylcholinesterase inhibition. , Studies with zebrafish embryos/larvae have shown that MEHP can induce more severe developmental toxicity than DEHP at equivalent concentrations. , Rodent studies demonstrate MEHP preferentially accumulated in brain tissue at concentrations exceeding DEHP and induced systemic inflammation. Our histopathological analysis demonstrated MEHP-induced neurodegeneration in adolescent rat hippocampus, including pyknotic nuclei, necrotic foci, and markedly reduced Nissl body density (Figure ). Consistent with this, behavioral and transcriptomic analyses confirmed MEHP neurotoxicity in adolescent rats. This neurotoxicity is characterized by spatial learning/memory deficits, establishing these impairments as conserved phenotypic responses to MEHP exposure in rodents. Based on previous literature, brain cell apoptosis and neuroinflammatory responses have been implicated as potential underlying causes of MEHP-induced neurotoxicity in adolescent mice.

Spatial learning and memory are critically mediated by hippocampal circuits within the limbic system. Neuronal pathology was observed in hippocampal CA3 and CA1 subfields following the MEHP exposure in our study. Notably, histopathological analysis revealed more severe lesions in CA3 versus CA1 (Figure ), consistent with CA3′s specialized role in spatial pattern completion versus CA1’s integration of spatiotemporal signals. Nissl staining is routinely employed to quantify neuronal integrity, where damage correlates with reduced Nissl body density. MEHP exposure considerably reduced Nissl body density in the hippocampus, indicating compromised neuronal function. This finding aligns with DEHP-induced Nissl body reduction in murine hippocampus, confirming conserved neurotoxicity across species.

Synaptic plasticity denotes activity-dependent modification of synaptic strength. Dysregulation of synaptic plasticity constitutes a fundamental mechanism underlying anxiety-like behaviors. SYP regulates synaptic vesicle exocytosis, while PSD-95 scaffolds glutamate receptors at postsynaptic densities, facilitating neurotransmission efficacy. , The expression levels of SYP and PSD-95 critically modulate synaptic plasticity and cognitive function. In our study, the high-dose MEHP (50 mg/kg) exposure remarkably decreased hippocampal PSD-95 expression in offspring, while SYP levels remained unchanged. Complementary H&E staining demonstrated concurrent neuronal pathology, including increased nuclear basophilia and disrupted laminar organization. Collectively, these structural and molecular alterations underlie spatial navigation deficits, demonstrating that MEHP disrupts hippocampal network integrity through convergent mechanisms.

Myelin is fundamental for learning and memory, with its degradation characterizing numerous neurological disorders featuring cognitive impairment. Loss of myelin exerts profoundly negative effects on axonal function and neuronal connectivity. Evidence suggests myelin critically supports cognitive function through enhancing information processing via maintained neural circuit connectivity and optimized conduction velocity. , MBP, one of the most abundant structural proteins in myelin, is essential for maintaining myelin compaction. In our study, the developmental high-dose MEHP exposure (50 mg/kg) obviously reduced the MBP expression (Figure ). This reduction correlated with hippocampal-dependent cognitive deficits, reflected in diminished target platform exploration and reduced target quadrant dwell time during MWM probe trials (Figure ).

Cytochromes, predominantly CYP450 enzymes  including associated redox partners such as cytochrome b5, NADPH–CYP450 reductase, and various electron transfer systems  are ubiquitously expressed in mammalian cells. CYP450 enzymes are involved in the biomediation and biodegradation of MEHP to counteract exogenous brain injury, while also mediating endogenous substance metabolism. Transcriptomic analysis revealed marked enrichment of CYP450-associated pathways in MEHP-exposed brain tissues through GO and KEGG analyses, identifying them as key targets of MEHP neurotoxicity. Subsequent RT-qPCR validation confirmed that CYP450-related gene expression (e.g., Cyp2a1, Cyp2f4, Cyp2g1, and Cyp1a2) was downregulated by the MEHP exposure. Enzymes encoded by CYP450 genes participate in the biosynthesis and metabolism of diverse intracellular chemicals. Generally, mutations in CYP450 genes are known to impair enzyme functionality. Global studies have reported that CYP450 expression levels and CYP450-dependent enzyme activities are modulated by environmental pollutants. , For instance, atrazine has been shown to disrupt CYP450 homeostasis in quail brains. Genetic polymorphisms in the aryl hydrocarbon receptor (AhR) and CYP1A2 influence an organism’s susceptibility to developmental polychlorinated biphenyl exposure, thereby contributing to cognitive deficits and motor dysfunction. Sustained nitric oxide accumulation in murine neurons led to diminished CYP1A2 induction capacity, suggesting that neurodegenerative processes may compromise the metabolic capability of the central nervous system toward exogenous/endogenous chemicals, potentially facilitating the pathogenesis of neurological disorders. Cannabidiol alleviated pain-related behaviors and depressive states in mice, likely mediated through modulation of targets such as CYP1A2. However, data on the MEHP’s effects on CYP450 gene expression in offspring brains remain scarce. In this study, developmental MEHP exposure was found to downregulate CYP450 genes (Cyp2a1, Cyp2f4, Cyp2g1, and Cyp1a2) in offspring brains. These findings demonstrate that MEHP alters CYP450 transcription in rat brains, a critical mechanism underlying its neurotoxicity.

The expression of metabolic enzymes and transport proteins is a key determinant of the body’s innate defense mechanisms against xenobiotics. A central mechanism of this defense system involves the transcriptional activation and upregulation of these enzymes and transporters in response to xenobiotic exposure. Nuclear xenobiotic receptors (NXRs) play pivotal roles in this process. NXRs are known to induce the transcription of CYP450 isozymes through competitive interactions, which are modulated by exogenous substances. The expression of numerous genes involved in xenobiotic metabolism, including those mediating the metabolism and transport of DEHP and MEHP, is regulated by at least three nuclear receptors or xenobiotic sensors: AHR, CAR, and PXR. DEHP activates the CAR pathway, inducing multiple hepatic target genes in vivo. , The CAR-mediated effects of DEHP provide a novel mechanistic framework for explaining previously reported phthalate toxicities, including endocrine disruption, hepatocellular carcinoma, and metabolic syndrome. Previous studies have demonstrated that several phthalate monoesters, including MEHP and MBzP, stimulate the transcriptional activity of PXR. Cyp1a1, Cyp1b1, and Cyp1a2regulated by AHRparticipate in xenobiotic metabolism. However, our study found that the MEHP exposure did not markedly alter the mRNA expression of AHR, CAR, or PXR in offspring rats. This finding contrasts with previous reports, suggesting that the MEHP’s neurotoxic mechanisms operate independently of the PXR/CAR and AHR pathways.

5. Conclusions

This study reveals that developmental exposure to MEHP induces hippocampal neuronal damage and adolescent neurobehavioral deficits through direct suppression of CYP450 transcriptiona neuroprotective pathway identified as operating independently of canonical xenobiotic-sensing receptors. Vulnerable populations, such as pregnant women and infants, face heightened risks due to widespread occurrence of phthalates in the environment. The link between CYP450 dysregulation and behavioral impairments underscores a critical window of susceptibility during early life exposure. These findings necessitate integrating CYP450 activity biomarkers into neurotoxicity risk assessments and enforcing stricter controls on the phthalate use in consumer products. Concurrently, accelerating the development of biobased phthalate alternatives is imperative to mitigate environmental contamination and safeguard long-term neurodevelopmental health. Global regulatory frameworks must prioritize re-evaluating safety thresholds for endocrine-disrupting chemicals to address this urgent public health challenge.

Supplementary Material

eh5c00171_si_001.pdf (346.7KB, pdf)

Acknowledgments

This work was jointly supported by the National Natural Science Foundation of China (22225605 and 22193051), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0750200), and the National Key Research and Development Program of China (2023YFC3706600).

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/envhealth.5c00171.

  • Details of materials and methods; protocols for animal experiments, behavioral tests, H&E and Nissl staining, immunohistochemistry, RNA sequencing, and RT-qPCR analysis; list of primer sequences; DEGs of related genes in RNA-Seq results; and RNA-seq analysis of brain tissue (PDF)

The authors declare no competing financial interest.

Published as part of Environment & Health special issue “New Pollutants: Challenges and Prospects”.

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