Research indicates DEHP exposure increases anxiety in male rats, reversible by GABA and testosterone — Evidence Review

Male rats exposed early in life to a common plastic chemical, DEHP, exhibited increased anxiety as adults—a finding from the University of Buenos Aires School of Medicine that aligns with prior animal studies linking phthalate exposure to behavioral changes. Related research generally supports these results, consistently demonstrating anxiety-like effects after early DEHP exposure and highlighting the role of hormonal and neurochemical pathways.

• Multiple studies in rodents report that perinatal or prenatal DEHP exposure leads to anxiety- and depression-like behaviors in adulthood, with hormonal disruptions (e.g., lowered testosterone, altered estrogen signaling) implicated in these effects 1 2 3 4.
• Similar behavioral changes—such as increased anxiety in elevated plus maze tests—have been reversed by administering testosterone or GABAergic agents, suggesting a mechanistic overlap with the new study's findings 3 7 8 10.
• Evidence also points to broader neurobehavioral impacts from plastic additives, including microplastics and other phthalates, with potential relevance to human health and transgenerational effects 4 11 12 13.

Study Overview and Key Findings

Rising concerns about widespread plasticizer exposure and its potential health impacts have driven research into the neurobehavioral effects of chemicals like DEHP, commonly found in everyday products. The study presented at ENDO 2026 is notable for isolating the effects of early-life DEHP exposure on adult anxiety in male rats and for demonstrating that both GABAergic and androgenic interventions can reverse these effects. This research adds mechanistic insight to a field where epidemiological evidence in humans remains limited but animal studies are accumulating.

Property	Value
Study Year	2026
Organization	University of Buenos Aires School of Medicine
Authors	Osvaldo Juan Ponzo, M.D., Ph.D.
Population	Male rats
Methods	Animal Study
Outcome	Anxiety-related behavior, effects of GABA and testosterone
Results	DEHP exposure increased anxiety; GABA and testosterone reversed effects.

Literature Review: Related Studies

To contextualize these findings, we searched the Consensus paper database, which indexes over 200 million research papers. The following queries were used to identify relevant studies:

1. DEHP anxiety exposure effects
2. GABA testosterone anxiety reversal
3. plastic chemicals mental health outcomes

Topic	Key Findings
How does early-life DEHP exposure impact anxiety and neurobehavioral outcomes?	- Early (perinatal/prenatal) DEHP exposure increases anxiety- and depression-like behaviors in rodents, with effects persisting into adulthood 1 2 3 4. - These behavioral changes are often accompanied by alterations in neuroendocrine signaling, including reduced testosterone and disrupted estrogen receptor expression 1 2 3.
Can hormonal or neurochemical interventions reverse anxiety induced by DEHP?	- Testosterone replacement after DEHP exposure restores normal anxiety-like behavior in male rats, implicating androgenic pathways 3 6 7 8 9. - GABA agonists reverse anxiety and neuroendocrine disruption caused by DEHP, highlighting the role of inhibitory neurotransmission 10.
What are the broader implications of plastic additives on neurodevelopment and health?	- Microplastics and additives like DEHP are linked to neurotoxicity, oxidative stress, and behavioral changes in animal models, with some evidence of transgenerational and cognitive impacts 4 11 12 13 14 15. - Human health effects are suggested by epidemiological studies, with DEHP exposure associated with increased mortality and cognitive deficits 13 11.
Are the behavioral and neuroendocrine effects of DEHP sex-specific or transgenerational?	- DEHP's effects on anxiety and neuroendocrine markers often differ by sex, with males particularly susceptible to antiandrogenic actions and females affected through altered estrogen signaling 1 3 5. - Some studies report that DEHP-induced behavioral and physiological changes can persist across generations via germline transmission 4.

How does early-life DEHP exposure impact anxiety and neurobehavioral outcomes?

Research broadly supports the finding that perinatal or prenatal DEHP exposure increases anxiety-like behaviors in rodents, often measured through tests such as the elevated plus maze. These effects are observed in both mice and rats and can persist into adult life. The new study aligns with this literature, further detailing long-term behavioral consequences of early DEHP exposure.

• Perinatal DEHP exposure in mice and rats results in increased anxiety and depression-like behaviors, regardless of sex in some studies 1 3.
• Behavioral changes are often associated with disruption of gonadal hormone signaling, including reductions in androgen or estrogen receptor expression 1 2 3 5.
• Neurobehavioral effects can include impaired memory and social behaviors, not just anxiety 2 4 5.
• Some studies indicate that these behavioral effects may be mediated by neurodegeneration or oxidative stress in brain areas such as the hippocampus 2.

Can hormonal or neurochemical interventions reverse anxiety induced by DEHP?

Evidence indicates that both testosterone and GABAergic interventions are effective in reversing anxiety-like behaviors induced by DEHP exposure. This supports the new study's finding that administering GABA agonists or testosterone can normalize anxiety-related behavior in DEHP-exposed male rats.

• Testosterone replacement after DEHP exposure restores normal anxiety-related behaviors, supporting an antiandrogenic mechanism 3 6 7 8 9.
• GABA agonists (e.g., muscimol, baclofen) reverse both behavioral and neuroendocrine disruptions caused by DEHP, underscoring the role of inhibitory neurotransmission 10.
• Testosterone’s anxiolytic effects in rodents are rapid and may involve conversion to neurosteroids that modulate GABA(A) receptors 6 7 8 9.
• The interplay between androgen receptors, GABAergic signaling, and anxiety is complex, and may involve both direct and indirect mechanisms 8 9 10.

What are the broader implications of plastic additives on neurodevelopment and health?

Research extends beyond DEHP to consider other plastic additives and microplastics, which are implicated in a variety of neurodevelopmental, cognitive, and health outcomes in both animal models and epidemiological studies. The current study adds to a growing body of evidence suggesting that environmental plasticizers can have lasting neurobehavioral effects.

• Microplastics and their additives are linked to neurotoxicity, oxidative stress, mitochondrial dysfunction, and altered behavior in animal models 11 12 14 15.
• Some studies suggest that these effects can persist over multiple generations, indicating possible epigenetic or germline transmission 4.
• Epidemiological data associate DEHP exposure with increased mortality, cognitive impairment, and adverse health outcomes in humans 13 11.
• The complex mixture of chemicals in plastics, including phthalates and bisphenol A, complicates attribution of effects to single compounds 11 13 15.

Are the behavioral and neuroendocrine effects of DEHP sex-specific or transgenerational?

Several studies report that the effects of DEHP are not uniform across sexes and may even be passed down transgenerationally. This highlights the importance of considering both sex differences and potential long-term reproductive and behavioral consequences.

• Male rodents are particularly susceptible to DEHP’s antiandrogenic and anxiogenic effects, while females may be affected through altered estrogen signaling 1 3 5.
• Transgenerational studies indicate that anxiety-like behaviors and changes in reproductive markers can persist in subsequent generations 4.
• Sex-specific effects are observed in hormone levels, receptor expression, and behavioral outcomes after DEHP exposure 1 3 5.
• The mechanisms underlying these differences may involve both direct endocrine disruption and epigenetic modifications 4.

Future Research Questions

While animal studies provide strong evidence for the behavioral and neuroendocrine impacts of early-life DEHP exposure, significant questions remain regarding mechanisms, human relevance, and long-term outcomes. Addressing these gaps will require interdisciplinary research spanning molecular, behavioral, and epidemiological domains.

Research Question	Relevance
Does early-life DEHP exposure cause long-term anxiety effects in humans?	Most evidence is from animal studies; the degree to which these findings translate to human populations is unclear and requires epidemiological investigation 1 2 4 13.
What molecular mechanisms mediate anxiety after DEHP exposure?	Understanding how DEHP interacts with hormone and neurotransmitter systems will clarify targets for prevention and intervention 2 3 7 8 9 10.
Are the effects of DEHP on anxiety transgenerational?	Evidence suggests some behavioral and physiological effects persist across generations in rodents, implicating possible epigenetic mechanisms 4.
How do sex differences influence DEHP-induced anxiety?	Several studies report sex-specific effects; elucidating these differences will inform risk assessment and targeted interventions 1 3 5.
Can lifestyle or pharmacological interventions mitigate the behavioral effects of plastic chemical exposure?	Treatments such as testosterone or GABA agonists reverse anxiety in animal models; determining whether similar strategies are effective and safe in humans is important for clinical translation 3 7 8 10.