Non-monotonic dose effects of in utero exposure to di(2-ethylhexyl) phthalate (DEHP) on testicular and serum testosterone and anogenital distance in male mouse fetuses

Do, Rylee Phuong; Stahlhut, Richard W.; Ponzi, Davide; vom Saal, Frederick S.; Taylor, Julia A.

doi:10.1016/j.reprotox.2012.09.006

Cited by 121Effects and risks of endocrine disrupting chemicalsSexual Differentiation and DisordersPesticide Exposure and Toxicity

Non-monotonic dose effects of in utero exposure to di(2-ethylhexyl) phthalate (DEHP) on testicular and serum testosterone and anogenital distance in male mouse fetuses

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Do, Rylee Phuong, Stahlhut, Richard W., Ponzi, Davide, vom Saal, Frederick S., Taylor, Julia A.·2012·Reproductive Toxicology

DOI 10.1016/j.reprotox.2012.09.006PMC PMC3543148

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Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant. Epidemiological studies suggest that DEHP decreases masculinization of male fetuses. Numerous rat studies report DEHP reduces fetal testosterone production at doses greatly exceeding human exposure. We fed pregnant CD-1 mice 0.5-500,000 μg/kg/day DEHP from gestation day (GD) 9-18 and examined mothers and male fetuses on GD 18. We assessed non-monotonic dose-response by adding a quadratic term to a simple linear regression model. Except at the 500,000 μg/kg/day dose, DEHP stimulated an increase in maternal and fetal serum testosterone and increased anogenital distance (AGD). Non-monotonic dose-response curves were noted for AGD and maternal, and testis testosterone (P values 0.013-0.021). Because data from our highest dose (500,000 μg/kg/day) did not differ significantly from controls, this dose could have been incorrectly assumed to be the NOAEL had we only tested very high doses, as is typical in studies for regulatory agencies.

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In male mice, gestational administration of Di(2-ethylhexyl) phthalate, an estrogenic chemical, increases fetal testosterone, AGD and AGI at very low doses but not at higher ones.
“a study by Do et al. [62] showed that in male mice gestational administration of Di(2-ethylhexyl) phthalate, an estrogenic chemical, increases fetal testosterone, AGD and AGI at very low doses but not at higher ones.”
From Developmental exposure to low levels of ethinylestradiol affects social play in juvenile male rats (2020) · cites this paper as [62]
The Discussion (page unavailable) reports elevated fetal serum testosterone at low DEHP doses and increased testicular testosterone and AGD in a subset of male fetuses; the highest dose did not differ from controls for the latter measures. Results §3.9 (page unavailable) reports a non-linear effect on weight-adjusted AGD, which may correspond to the claim’s AGI, but does not call it AGI. The copy does not characterize DEHP as an estrogenic chemical, and the AGD and testicular-testosterone findings are specifically for 1MF males, not all male fetuses. (LLM, conf=0.87)
Experimental — accuracy not yet measured
The dose-effect relationship observed in this study is non-linear.
“The dose–effect relationship observed in our study is non-linear, confirming that at very low doses, hormonally active substances may have non-linear effects [62].”
From Developmental exposure to low levels of ethinylestradiol affects social play in juvenile male rats (2020) · cites this paper as [62]

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Non-monotonic eose effects of in utero exposure to di(2-ethylhexyl) phthalate (DEHP) on testicular and serum testosterone and anogenital distance in male mouse fetuses
Do, R. (2012) · MOspace Institutional Repository (University of Missouri)
Self-citation
A dose–response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): Effects on androgenic status, developmental landmarks and testicular histology in male offspring rats
Martino‐Andrade, A. J., Grande, S. W., Talsness, C. E., Grote, K., Golombiewski, A., Sterner‐Kock, A., & Chahoud, I. (2006) · Toxicology · doi:10.1016/j.tox.2006.05.007 · Cited by 106 · see citing works
A dose response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): Reproductive effects on adult male offspring rats
Martino‐Andrade, A. J., Grande, S. W., Talsness, C. E., Gericke, C., Grote, K., Golombiewski, A., Sterner‐Kock, A., & Chahoud, I. (2006) · Toxicology · doi:10.1016/j.tox.2006.08.020 · Cited by 152 · see citing works
A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP): Effects on reproductive development and function of male offspring rats
Martino‐Andrade, A. J. (2007) · Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver · doi:10.17169/refubium-14040 · Cited by 1 · see citing works
Gestational di(2-ethylhexyl) phthalate alters pregnancy outcomes, growth, biochemical, hematological, and reproductive hormone profiles in male offspring mice
Zaman, H., Haque, M., Mobarak, M. H., Sabuz, S. H., Basher, M. K., Rahman, M., & Islam, M. (2026) · Journal of Advanced Biotechnology and Experimental Therapeutics · doi:10.5455/jabet.2026.40

Authors: Do, R. P., Stahlhut, R. W., Ponzi, D., vom Saal, F. S., & Taylor, J. A.
Affiliations: University of Rochester Medicine (US)
University of Missouri (US)
Corresponding author: Taylor, Julia A.
ORCID: Stahlhut, Richard W.
Taylor, Julia A.
Venue: Reproductive Toxicology
Publisher: Elsevier BV
Published: 2012-12
Volume: 34
Issue: 4
Pages: 614-621
ISSN: 0890-6238 (ISSN-L)
DOI: 10.1016/j.reprotox.2012.09.006
PMC: PMC3543148
OpenAlex: W2023158177
Cited by: 121
References: 49
Citations by year: 2026: 3 · 2025: 5 · 2024: 6 · 2023: 9 · 2022: 10 · 2021: 11 · 2020: 10 · 2019: 18 · 2018: 6 · 2017: 12 · 2016: 6 · 2015: 12 · 2014: 5 · 2013: 7 · 2012: 1
FWCI: 5.55
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Reproductive Toxicology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Environmental Health Sciences (R01ES021394)
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
Life Sciences › Agricultural and Biological Sciences › Plant Science › Pesticide Exposure and Toxicity
Keywords: DEHP, non-monotonic dose-response, prenatal exposure, fetal testosterone, testicular testosterone, anogenital distance, masculinization, endocrine disruptors, no-observed-adverse-effect level, developmental toxicity
MeSH terms: Animals, Anal Canal, Diethylhexyl Phthalate, Dose-Response Relationship, Drug, Female, Genitalia, Male, Male, Maternal-Fetal Exchange, Plasticizers, Pregnancy, Testis, Testosterone, Animals, Outbred Strains, Mice, Endocrine Disruptors

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Non-monotonic dose effects of in utero exposure to di(2-ethylhexyl) phthalate (DEHP) on testicular and serum testosterone and anogenital distance in male mouse fetuses

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