Evaluation of ovarian toxicity of mono-(2-ethylhexyl) phthalate (MEHP) using cultured rat ovarian follicles

Ishiguro, Hiroshi; Chihara, Kazuhiro; Yamashita, Akihito; Miyawaki, Izuru; Fukuda, Chiharu; Tateishi, Yumi; Kunimatsu, Takeshi; Kimura, Juki; Funabashi, Hitoshi; Miyano, Takashi

doi:10.2131/jts.37.483

Cited by 52 publications

(34 citation statements)

References 25 publications

(23 reference statements)

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“…In our experiments, the rate of total apoptosis (including early and late apoptosis) was significantly increased in the presence of 50 mol/l and 100 mol/l MEHP. Similarly, Inada et al reported that 100 g/ml MEHP suppressed the development of rat ovarian follicles, associated with apoptosis of granulosa cells (Inada et al, 2012). From the effects of MEHP on granulosa cell viability and apoptosis, we conclude that MEHP may inhibit granulosa cell proliferation through inducing apoptosis.…”

Section: Discussionsupporting

confidence: 69%

The effect of mono-(2-ethylhexyl) phthalate on apoptosis of rat ovarian granulosa cells in vitro

Liu

Yuan

et al. 2015

Environmental Toxicology and Pharmacology

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Section: Discussionsupporting

confidence: 69%

The effect of mono-(2-ethylhexyl) phthalate on apoptosis of rat ovarian granulosa cells in vitro

Liu

Yuan

et al. 2015

Environmental Toxicology and Pharmacology

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“…These results show that we can evaluate the direct effects of VPA on the ovarian morphology, including follicular development, and on the overall synthetic pathway of steroid hormones, without respect to the feedback system in the hypothalamicpituitary-ovarian axis, in a short time with a small amount of chemical using this method. Additionally, we reported ovarian toxicity of MEHP using a similar culture system of rat ovarian follicles in our previous study (Inada et al, 2012). Taken together, the method using cultured rat ovarian follicles is considered useful to evaluate the potential ovarian toxicity of medicinal compounds and chemicals including medicinal products.…”

Section: Discussionmentioning

confidence: 86%

“…We have evaluated the direct effects of mono-(2-ethylhexyl) phthalate (MEHP) on rat ovarian follicles cultured for the treatment period of 48 hr, and found its ovarian toxicity via suppression of follicular development and abnormal steroid hormone synthesis (Inada et al, 2012). The present study was conducted to evaluate the effects of VPA on the follicular development and steroid hormone synthesis using cultured rat ovarian follicles.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of ovarian toxicity of sodium valproate (VPA) using cultured rat ovarian follicles

et al. 2012

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-Sodium valproate (VPA) is a major antiepileptic drug that is widely used for the treatment of epilepsy as well as other neuropsychiatric diseases. The present study was conducted to evaluate the ovarian toxicity of VPA using cultured rat ovarian follicles. Secondary follicles were isolated from the ovaries of 14-day-old female rats and cultured for 48 hr with VPA (0, 0.2, 1.0, and 5.0 mM). At 0, 24, and 48 hr of VPA treatment, follicular diameters were measured. After the culture, viability of follicles and expression of aromatase in the follicles were assessed, and progesterone, androstenedione, testosterone, and estradiol levels in culture media were measured. At all concentrations of VPA, follicular development was suppressed, and androstenedione, testosterone, estradiol, and combined levels of all steroid hormones tended to decrease in association with suppression of aromatase expression in granulosa cells. Additionally, the suppression of follicular development was associated with decreased viability of follicles and an increased progesterone level at 5.0 mM of VPA. The decrease in the combined levels of all steroid hormones implies that VPA suppresses the synthetic pathway from cholesterol to estradiol including de novo synthesis of cholesterol. In conclusion, VPA induces ovarian toxicity via suppression of development and abnormal steroid hormone synthesis in cultured rat ovarian follicles.

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“…Likewise, MEHP exposure has also been shown to decrease estradiol levels in cultured ovarian cell types and follicles in vitro [16,[19][20][21]53]. However, the mechanism by which MEHP decreases estradiol levels is unknown.…”

Section: Effect Of Mehp On Sex Steroid Hormone Production By Antral Fmentioning

confidence: 99%

“…Previous studies have determined that MEHP exposure decreases estradiol levels in vitro; however, these studies utilized secondary follicles or murine/human granulosa cells [19][20][21]53]. Ovarian steroidogenesis is primarily conducted by the mature antral follicle, and it involves the strict coordination of theca and granulosa cells.…”

Section: Mehp Disrupts Folliculogenesis and Steroidogenesismentioning

confidence: 99%

Mono(2-Ethylhexyl) Phthalate Accelerates Early Folliculogenesis and Inhibits Steroidogenesis in Cultured Mouse Whole Ovaries and Antral Follicles1

Hannon

Brannick

Wang

et al. 2015

Biology of Reproduction

108

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Humans are ubiquitously exposed to di(2-ethylhexyl) phthalate (DEHP), which is an environmental toxicant present in common consumer products. DEHP potentially targets the ovary through its metabolite mono(2-ethylhexyl) phthalate (MEHP). However, the direct effects of MEHP on ovarian folliculogenesis and steroidogenesis, two processes essential for reproductive and nonreproductive health, are unknown. The present study tested the hypotheses that MEHP directly accelerates early folliculogenesis via overactivation of phosphatidylinositol 3-kinase (PI3K) signaling, a pathway that regulates primordial follicle quiescence and activation, and inhibits the synthesis of steroid hormones by decreasing steroidogenic enzyme levels. Neonatal ovaries from CD-1 mice were cultured for 6 days with vehicle control, DEHP, or MEHP (0.2-20 lg/ml) to assess the direct effects on folliculogenesis and PI3K signaling. Further, antral follicles from adult CD-1 mice were cultured with vehicle control or MEHP (0.1-10 lg/ml) for 24-96 h to establish the temporal effects of MEHP on steroid hormones and steroidogenic enzymes. In the neonatal ovaries, MEHP, but not DEHP, decreased phosphatase and tensin homolog levels and increased phosphorylated protein kinase B levels, leading to a decrease in the percentage of germ cells and an increase in the percentage of primary follicles. In the antral follicles, MEHP decreased the mRNA levels of 17alpha-hydroxylase-17,20-desmolase, 17beta-hydroxysteroid dehydrogenase, and aromatase leading to a decrease in testosterone, estrone, and estradiol levels. Collectively, MEHP mediates the effect of DEHP on accelerated folliculogenesis via overactivating PI3K signaling and inhibits steroidogenesis by decreasing steroidogenic enzyme levels.

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Evaluation of ovarian toxicity of mono-(2-ethylhexyl) phthalate (MEHP) using cultured rat ovarian follicles

Cited by 52 publications

References 25 publications

The effect of mono-(2-ethylhexyl) phthalate on apoptosis of rat ovarian granulosa cells in vitro

The effect of mono-(2-ethylhexyl) phthalate on apoptosis of rat ovarian granulosa cells in vitro

Evaluation of ovarian toxicity of sodium valproate (VPA) using cultured rat ovarian follicles

Mono(2-Ethylhexyl) Phthalate Accelerates Early Folliculogenesis and Inhibits Steroidogenesis in Cultured Mouse Whole Ovaries and Antral Follicles1

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