Di(2-ethylhexyl) phthalate inhibits antral follicle growth, induces atresia, and inhibits steroid hormone production in cultured mouse antral follicles

Patrick R. Hannon, Katherine E. Brannick, Wei Wang, Rupesh K. Gupta, Jodi A. Flaws

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental toxicant found in consumer products that causes ovarian toxicity. Antral follicles are the functional ovarian units and must undergo growth, survival from atresia, and proper regulation of steroidogenesis to ovulate and produce hormones. Previous studies have determined that DEHP inhibits antral follicle growth and decreases estradiol levels in vitro; however, the mechanism by which DEHP elicits these effects is unknown. The present study tested the hypothesis that DEHP directly alters regulators of the cell cycle, apoptosis, and steroidogenesis to inhibit antral follicle functionality. Antral follicles from adult CD-1 mice were cultured with vehicle control or DEHP (1-100. μg/ml) for 24-96. h to establish the temporal effects of DEHP on the follicle. Following 24-96. h of culture, antral follicles were subjected to gene expression analysis, and media were subjected to measurements of hormone levels. DEHP increased the mRNA levels of cyclin D2, cyclin dependent kinase 4, cyclin E1, cyclin A2, and cyclin B1 and decreased the levels of cyclin-dependent kinase inhibitor 1A prior to growth inhibition. Additionally, DEHP increased the mRNA levels of BCL2-associated agonist of cell death, BCL2-associated X protein, BCL2-related ovarian killer protein, B-cell leukemia/lymphoma 2, and Bcl2-like 10, leading to an increase in atresia. Further, DEHP decreased the levels of progesterone, androstenedione, and testosterone prior to the decrease in estradiol levels, with decreased mRNA levels of side-chain cleavage, 17α-hydroxylase-17,20-desmolase, 17β-hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis.

Original languageEnglish
Pages (from-to)42-53
Number of pages12
JournalToxicology and Applied Pharmacology
Volume284
Issue number1
DOIs
StatePublished - Apr 1 2015

Bibliographical note

Funding Information:
The authors thank Dr. Ayelet Ziv-Gal, Dr. Liying Gao, and Shreya Patel for assistance with follicle isolations, and the authors thank all members of Dr. Flaws' laboratory for the technical assistance. This work was supported by the National Institute of Environmental Health Sciences grant R01ES019178 (JAF) and an Interdisciplinary Environmental Toxicology Program Fellowship (PRH).

Publisher Copyright:
© 2015 Elsevier Inc.

Keywords

  • Antral follicle
  • Atresia
  • Di(2-ethylhexyl) phthalate
  • Ovary
  • Steroidogenesis

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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