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Cited by 34Effects and risks of endocrine disrupting chemicalsSexual Differentiation and DisordersToxic Organic Pollutants Impact

Exposure to di-(2-ethylhexyl) phthalate transgenerationally alters anxiety-like behavior and amygdala gene expression in adult male and female mice

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Hatcher, Katherine M., Willing, Jari, Chiang, Catheryne, Rattan, Saniya, Flaws, Jodi A., Mahoney, Megan M.·2019·Physiology & Behavior
DOI 10.1016/j.physbeh.2019.04.018PMC PMC6545259
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Abstract

Phthalates are industrial plasticizers and stabilizers commonly found in polyvinyl chloride plastic and consumer products, including food packaging, cosmetics, medical devices, and children's toys. Di-(2-ethylhexyl) phthalate (DEHP), one of the most commonly used phthalates, exhibits endocrine-disrupting characteristics and direct exposure leads to reproductive deficits and abnormalities in anxiety-related behaviors. Importantly, increasing evidence indicates that the impacts of DEHP exposure on reproduction and social behavior persist across multiple generations. In this study, we tested the hypothesis that transgenerational DEHP exposure alters anxiety-like behavior and neural gene expression in both male and female mice. Pregnant CD-1 mice were orally dosed daily with either tocopherol-stripped corn oil or DEHP (20 or 200 μg/kg/day; 500 or 750 mg/kg/day) from gestational day 10.5 until birth to produce the F1 generation. Females from each generation were bred with untreated, unrelated CD-1 males to produce subsequent generations. Behavior and gene expression assays were performed with adult, intact F3 males and females. Transgenerational DEHP exposure increased time spent in the open arm in the elevated plus maze for adult females (750 mg/kg/day lineage), but not males. In adult females, we observed a down-regulation of mRNA expression of estrogen receptor 1 in the 200 μg/kg/day and 500 mg/kg/day treatment lineages, mineralocorticoid receptor in the 200 μg/kg/day lineage, and dopamine receptor 2 in the 20 μg/kg/day and 750 mg/kg/day lineages. In adult males, we found an up-regulation of estrogen receptor 2 in the 20 and 200 μg/kg/day lineages, and dopamine receptor 1 in the 20 μg/kg/day and 750 mg/kg/day lineages. No hippocampal gene expression modifications were observed in response to treatment. These results implicate dose-specific transgenerational effects on behavior and neural gene expression in adult male and female mice.

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  • DEHP exposure during pregnancy and lactation alters the expression of pituitary hormones and hypothalamic-pituitary-adrenal axis-related stress hormones across generations, accompanied by social behavioral abnormalities in descendants that were not directly exposed.

    “In the case of phthalates, DEHP exposure during pregnancy and lactation alters the expression of pituitary hormones and hypothalamic–pituitary–adrenal axis-related stress hormones across generations, and this is accompanied by social behavioral abnormalities in descendants that were not directly exposed (Hatcher et al., 2019; Quinnies et al., 2017).”

    From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Hatcher et al., 2019

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Authors
Hatcher, K. M., Willing, J., Chiang, C., Rattan, S., Flaws, J. A., & Mahoney, M. M.
Affiliations
University of Illinois Urbana-Champaign (US)
Corresponding author
Mahoney, Megan M.
ORCID
Venue
Physiology & Behavior
Publisher
Elsevier BV
Published
2019-08
Volume
207
Pages
7-14
ISSN
0031-9384 (ISSN-L)
DOI
10.1016/j.physbeh.2019.04.018
PMC
PMC6545259
OpenAlex
W2941976691
Cited by
34
References
9
Citations by year
2026: 1 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 5 · 2020: 4
FWCI
1.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Physiology & Behavior (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Environmental Protection Agency
  • College of Veterinary Medicine
  • University of Illinois at Urbana-Champaign
  • The Interdisciplinary Environmental Toxicology Program (NIH T32 ES007326)
  • Interdisciplinary Environmental Toxicology Program (KMH)
  • Billie A. Field Fellowship in Reproductive Biology
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Keywords
DEHP, transgenerational exposure, anxiety-like behavior, endocrine disruption, phthalates, estrogen receptor 1, estrogen receptor 2, mineralocorticoid receptor, dopamine D1 receptor, dopamine D2 receptor, sex differences, prenatal exposure, dose-dependent effects
MeSH terms
Amygdala, Animals, Anxiety, Behavior, Animal, Diethylhexyl Phthalate, Dose-Response Relationship, Drug, Female, Gene Expression Regulation, Hippocampus, Male, Pregnancy, RNA, Messenger, Sex Characteristics, Social Behavior, Down-Regulation, Receptors, Dopamine D2, Receptors, Mineralocorticoid, Maternal Exposure, Estrogen Receptor alpha, Mice, Endocrine Disruptors

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