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9 May 2017 Effects of in vitro exposure to dibutyl phthalate, mono-butyl phthalate, and acetyl tributyl citrate on ovarian antral follicle growth and viability
Lindsay M. Rasmussen, Nivedita Sen, Jahaira C. Vera, Xiaosong Liu, Zelieann R. Craig
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Abstract

Dibutyl phthalate (DBP) is present in consumer products and the coating of some oralmedications. Acetyl tributyl citrate (ATBC) has been proposed as an alternative to DBP because DBP causes endocrine disruption in animal models. Following ingestion, DBP is converted to its main metabolite mono-butyl phthalate (MBP) which has been detected in >90% of human follicular fluid samples. Previous studies show that DBP reduces the number of antral follicles present in the ovaries of mice. Thus, this study was designed to evaluate the effects of DBP, MBP, and ATBC on in vitro growth and viability of mouse ovarian antral follicles. Antral follicles were isolated from CD-1 females (PND32-37) and treated with vehicle, DBP, MBP, or ATBC (starting at 0.001 and up to 1000µg/ml for DBP; 24–72 h). Follicle diameter, ATP production, qPCR, and TUNEL were used to measure follicle growth, viability, cell cycle and apoptosis gene expression, and cell death-associated DNA fragmentation, respectively. While MBP did not cause toxicity, DBP exposure at ≥10µg/ml resulted in growth inhibition followed by cytoxicity at ≥500 µg/ml. ATBC increased the number of nongrowing follicles at 0.01 µg/ml and did not affect ATP production, but increased TUNEL positive area in treated follicles. Gene expression results suggest that cytotoxicity in DBP-treated follicles occurs via activation of cell cycle arrest prior to follicular death. These findings suggest that concentrations of DBP ≥10 µg/ml are detrimental to antral follicles and that ATBC should be examined further as it may disrupt antral follicle function at low concentrations.

Summary Sentence

DBP and ATBC exposures resulted in dose-specific follicle growth inhibition with high concentrations of DBP causing cytoxicity via activation of cyclin-dependent kinase inhibitors and subsequent apoptosis.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Lindsay M. Rasmussen, Nivedita Sen, Jahaira C. Vera, Xiaosong Liu, and Zelieann R. Craig "Effects of in vitro exposure to dibutyl phthalate, mono-butyl phthalate, and acetyl tributyl citrate on ovarian antral follicle growth and viability," Biology of Reproduction 96(5), 1105-1117, (9 May 2017). https://doi.org/10.1095/biolreprod.116.144691
Received: 11 November 2016; Accepted: 10 January 2017; Published: 9 May 2017
JOURNAL ARTICLE
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