Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-ovarian axis in adult female rats

Liu, Te; Li, Na; Zhu, Jian; Yu, Ge; Guo, Kun; Zhou, Liting; Zheng, Dongchun; Qu, Xiaofeng; Huang, Jian; Chen, Xin; Wang, Shuyue; Lin, Ye

doi:10.1016/j.reprotox.2014.03.006

Cited by 60 publications

(38 citation statements)

References 40 publications

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“…Previous studies have determined that DEHP exposure decreases estradiol levels both in vivo [47-50] and in vitro [52, 53]. Similar to previous studies, we have reported that DEHP exposure for 96 hr decreases estradiol levels in an in vitro antral follicle culture system [54].…”

Section: Resultssupporting

confidence: 84%

“…Previous work has investigated the effects of DEHP exposure on antral follicle growth and steroidogenesis in vivo showing that DEHP decreased antral follicle diameter, and decreased the levels of serum estradiol produced by the antral follicles [47-50]. The limitation of these previous studies is that they did not determine whether the effects on antral follicle size and estradiol production were direct effects on the follicle or were indirect effects caused by toxicity in other organ systems, namely the hypothalamus-pituitary axis.…”

Section: Discussionmentioning

confidence: 99%

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

Hannon¹,

Brannick²,

Wang³

et al. 2015

Toxicology and Applied Pharmacology

133

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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 (1-100μg/ml) for 24-96 hr to establish the temporal effects of DEHP on the follicle. Following 24-96 hr 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-hydorxylase-17,20-desmolase, 17β-hydroxysteroid dehydrogenase, and aromatase. Collectively, DEHP directly alters antral follicle functionality by inhibiting growth, inducing atresia, and inhibiting steroidogenesis.

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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

Hannon¹,

Brannick²,

Wang³

et al. 2015

Toxicology and Applied Pharmacology

133

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“…DEHP may cause many adverse effects, in addition to reproductive toxicity or embryo toxicity [11][12][13], a possible regulating mechanism in the HPTA could account for the influence of thyroid. As previously demonstrated during growth of rats, TRH is regulated by the hypothalamic system to release into the pituitary and stimulate TSH production.…”

Section: Discussionmentioning

confidence: 99%

“…The biological effects of MEHP are hence of major concern; however, gaining an understanding of the underlying mechanistic events has posed several challenges. In the past, researches about DEHP mainly focused on reproductive defects [11][12][13]. More recently, greater attention has been paid on the thyroid toxic of DEHP.…”

mentioning

confidence: 99%

Correction and Republication: Effect of Di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-thyroid axis in adolescent rat

et al. 2018

Self Cite

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Abstract. Di-(2-ethylhexyl) phthalate (DEHP) is extensively used in many personal care and consumer products, which has resulted in widespread human exposure. Limited studies have suggested that exposure to DEHP may affect thyroid function, but little is known about the effect and mechanisms of DEHP exposure on the hypothalamic-pituitary-thyroid axis (HPTA). The present study was conducted to elucidate the potential mechanisms in which DEHP disrupts the function of the HPTA. Wistar rats were administered DEHP by gavage at 0, 5, 50, and 500 mg/kg/day for 28 days and then sacrificed within 24 h following the last dose. Hormones of HPTA was quantified with radioimmunoassay and enzyme-linked immunosorbent assay, protein levels of thyrotropin-releasing hormone receptor (TRHR) and thyroid-stimulating hormone receptor (TSHR) were analyzed by Western blot and immunohistochemistry, expression levels of TRHR and TSHR mRNA were measured by quantitative real-time PCR. Rats treated with DEHP resulted in increased bodyweight, on the HPTA, down-regulated the protein levels of TRH in the hypothalamus, up-regulated the protein and mRNA levels of TRHR in the pituitary, downregulated mRNA expression of TSHR in the thyroid, while the difference of TSH in various dose groups was not statistically significant and T3, T4, FT3, FT4 levels in serum were decreased compared with control. DEHP could interfere with the balance of HPTA of adolescent rats, and increase the body weight, down-regulate the homeostasis of thyroid related hormones and receptors expression levels. Correspondence to: Lin Ye, Department of Occupational and Environmental Health, School of Public Health, Jilin University, 1163 Xin Min Street, Changchun, 130021, China. E-mail: jlyelin@163.com *These authors equally contributed to this work. Abbreviations: DEHP, Di-(2-ethylhexyl) phthalate; EEDs, environmental endocrine disruptors; HPTA, hypothalamic-pituitary-thyroid axis; MEHP, mono-(2-ethylhexyl) phthalate; PAEs, Phthalic acid esters; PVC, polyvinyl chloride; QPCR, quantitative real-time PCR; THs, thyroid hormones; TRH, thyrotropin-releasing hormone; TRHR, thyrotropin-releasing hormone receptor; TSH, thyroidstimulating hormone; TSHR, thyroid-stimulating hormone receptor ambient air, water sources, and sediments [5][6][7]. Human exposure to PAEs mainly occurs through food due to the use of PVC in wrapping materials and food processing [1,8]. Once ingested through food contamination, di-(2-ethylhexyl) phthalate (DEHP), one of the most widely used and studied phthalates esters, is quickly metabolized to its monoester equivalent mono-(2-ethylhexyl) phthalate] (MEHP), which is preferentially absorbed [9,10]. The biological effects of MEHP are hence of major concern; however, gaining an understanding of the underlying mechanistic events has posed several challenges. In the past, researches about DEHP mainly focused on reproductive defects [11][12][13]. More recently, greater attention has been paid on the thyroid toxic of DEHP.The thyroid is the largest endocrine organ in h...

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“…1) being the most popular. However, the adverse developmental [3,4], reproductive [5,6], neurological [7] and immune [8] health effects of many phthalates has led to a search for alternative plasticizers. Other common small molecule plasticizers include terphthalates, 1,2-cyclohexane-dicarboxylic acid diisononyl ester (Hexamoll® DINCH®), epoxidized vegetable oils, citrates, mellitates, adipates, benzoates, maleates, succinates, sebacates, phosphates, isosorbide esters.…”

Section: Introductionmentioning

confidence: 99%

Phthalate plasticizers covalently linked to PVC via copper-free or copper catalyzed azide-alkyne cycloadditions

Earla

Costanzo

et al. 2017

Polymer

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Plasticization of PVC was carried out by covalently linking phthalate derivatives via copper-free (thermal) or copper catalyzed azide-alkyne cycloadditions. Di(2-ethylhexyl) phthalate derivatives (DEHPether and DEHP-ester) were synthesized and appended to PVC at two different densities. The glass transition temperatures of the modified PVC decreased with increasing content of plasticizer. PVC-DEHP-ether gave lower glass transition temperatures than PVC-DEHP-ester, reflecting the enhanced flexibility of the ether versus ester linker.

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Effects of di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-ovarian axis in adult female rats

Cited by 60 publications

References 40 publications

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

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

Correction and Republication: Effect of Di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-thyroid axis in adolescent rat

Phthalate plasticizers covalently linked to PVC via copper-free or copper catalyzed azide-alkyne cycloadditions

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