A mixture of five phthalate esters inhibits fetal testicular testosterone production in the Sprague-Dawley rat in a cumulative, dose-additive manner
Abstract
Phthalate diesters are chemicals to which humans are ubiquitously exposed. Exposure to certain phthalates during sexual differentiation causes reproductive tract malformations in male rats. In the fetal rat, exposure to the phthalates benzylbutyl phthalate (BBP), di(n)butyl phthalate (DBP), and diethylhexyl phthalate (DEHP) decreases testicular testosterone production and insulin-like 3 hormone mRNA levels. We characterized the dose-response effects of six individual phthalates (BBP, DBP, DEHP, diethyl phthalate [DEP], diisobutyl phthalate [DiBP], and dipentyl phthalate [DPP]) on gestation day (GD) 18 testicular testosterone production following exposure of Sprague-Dawley rats on GD 8-18. BBP, DBP, DEHP, and DiBP were equipotent (ED50 of 440 +/- 16 mg/kg/day), DPP was about threefold more potent (ED50 = 130 mg/kg/day) and DEP had no effect on fetal testosterone production. We hypothesized that coadministration of these five antiandrogenic phthalates would reduce testosterone production in a dose-additive fashion because they act via a common mode of toxicity. In a second study, dams were dosed at 100, 80, 60, 40, 20, 10, 5, or 0% of the mixture. The top dose contained 1300 mg of total phthalates/kg/day including BBP, DBP, DEHP, DiBP (300 mg/kg/day per chemical), and DPP (100 mg DPP/kg/day). This mixture ratio was selected such that each phthalate would contribute equally to the reduction in testosterone. As hypothesized, testosterone production was reduced in a dose-additive…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Animal studies have shown that phthalates inhibit testosterone production in the testicles.
“Animal studies have shown that phthalates inhibit testosterone production in the testicles (Howdeshell et al., 2008; Swan et al., 2005).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Howdeshell et al., 2008
Cites
Detection of Phthalate Metabolites in Human Amniotic Fluid
Silva, M. J., Reidy, J. A., Herbert, A. R., Preau, J. L., Needham, L. L., & Calafat, A. M. (2004) · Bulletin of Environmental Contamination and Toxicology · doi:10.1007/s00128-004-0374-4 · Cited by 302 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Braun, J. M., Kalkbrenner, A. E., Just, A. C., Yolton, K., Calafat, A. M., Sjödin, A., Hauser, R., Webster, G. M., Chen, A., & Lanphear, B. P. (2014) · Environmental Health Perspectives · doi:10.1289/ehp.1307261 · Cited by 328 · see citing works
Personal care products and endocrine disruption: A critical review of the literature
Witorsch, R. J., & Thomas, J. A. (2010) · Critical Reviews in Toxicology · doi:10.3109/10408444.2010.515563 · Cited by 334 · see citing works
Frederiksen, H., Jensen, T. K., Jørgensen, N., Kyhl, H. B., Husby, S., Skakkebæk, N. E., Main, K. M., Juul, A., & Andersson, A.-M. (2014) · Reproduction · doi:10.1530/rep-13-0522 · Cited by 219 · see citing works
Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development
Al-Gubory, K. H. (2014) · Reproductive BioMedicine Online · doi:10.1016/j.rbmo.2014.03.002 · Cited by 222 · see citing works
Sobolewski, M., Conrad, K., Allen, J. L., Weston, H., Martin, K., Lawrence, B. P., & Cory-Slechta, D. A. (2014) · NeuroToxicology · doi:10.1016/j.neuro.2014.09.008 · Cited by 91 · see citing works
Ouyang, X., Weiss, J. M., de Boer, J., Lamoree, M. H., & Leonards, P. E. G. (2017) · Chemosphere · doi:10.1016/j.chemosphere.2016.09.107 · Cited by 68 · 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
“Animal studies have shown that phthalates inhibit testosterone production in the testicles (Howdeshell et al., 2008; Swan et al., 2005).”
- Authors
- Howdeshell, K. L., Wilson, V. S., Furr, J., Lambright, C. R., Rider, C. V., Blystone, C. R., Hotchkiss, A. K., & Gray, L. E.
- Affiliations
- Environmental Protection Agency (US)
- Corresponding author
- Gray, Leon Earl
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-04-14
- Volume
- 105
- Issue
- 1
- Pages
- 153-165
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- OpenAlex
- W2166972916
- Cited by
- 441
- References
- 1
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 10 · 2023: 18 · 2022: 23 · 2021: 37 · 2020: 26 · 2019: 25 · 2018: 22 · 2017: 21 · 2016: 27 · 2015: 23 · 2014: 40 · 2013: 30 · 2012: 28
- FWCI
- 19.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- 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
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- phthalates, combined toxicity, butyl benzyl phthalate, dibutyl phthalate, DEHP, diisobutyl phthalate, diethyl phthalate, fetal testis, sexual differentiation, miscarriage, fetal death, reproductive tract malformations
- MeSH terms
- Animals, Body Weight, Dibutyl Phthalate, Diethylhexyl Phthalate, Dose-Response Relationship, Drug, Female, Fetus, Male, Phthalic Acids, Pregnancy, Testis, Testosterone, Logistic Models, Rats, Sprague-Dawley, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
