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Bisphenol A exposure during adulthood causes augmentation of follicular atresia and luteal regression by decreasing 17β-estradiol synthesis via downregulation of aromatase in rat ovary.

Lee SG, Kim JY, Chung JY, Kim YJ, Park JE, Oh S, Yoon YD, Yoo KS, Yoo YH, Kim JM - Environ. Health Perspect. (2013)

Bottom Line: Exposure to BPA significantly decreased E2 serum concentration, which was accompanied by augmented follicular atresia and luteal regression via increase of caspase-3-associated apoptosis in ovarian cells.However, P450scc and 3β-HSD protein levels remained unchanged.The steroidogenic proteins StAR and P450arom appear to be targeted by BPA.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan, Korea.

ABSTRACT

Background: Bisphenol A (BPA) has been detected in human body fluids, such as serum and ovarian follicular fluids. Several reports indicated that BPA exposure is associated with the occurrence of several female reproductive diseases resulting from the disruption of steroid hormone biosynthesis in the adult ovary.

Objective: We hypothesized that long-term exposure to low concentrations of BPA disrupts 17β-estradiol (E2) production in granulosa cells via an alteration of steroidogenic proteins in ovarian cells.

Methods: Adult female rats received BPA for 90 days by daily gavage at doses of 0, 0.001, or 0.1 mg/kg body weight. We determined serum levels of E2, testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). We also analyzed the expressions of steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase isomerase (3β-HSD), and aromatase cytochrome P450 (P450arom) in the ovary.

Results: Exposure to BPA significantly decreased E2 serum concentration, which was accompanied by augmented follicular atresia and luteal regression via increase of caspase-3-associated apoptosis in ovarian cells. After BPA exposure, P450arom and StAR protein levels were significantly decreased in granulosa cells and theca-interstitial (T-I) cells, respectively. However, P450scc and 3β-HSD protein levels remained unchanged. The increase in LH levels appeared to be associated with the decreased synthesis of T in T-I cells after BPA exposure via homeostatic positive feedback regulation.

Conclusions: BPA exposure during adulthood can disturb the maintenance of normal ovarian functions by reducing E2. The steroidogenic proteins StAR and P450arom appear to be targeted by BPA.

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Related in: MedlinePlus

Effect of BPA exposure on P450arom in granulosa cells and StAR, P450scc, and 3β-HSD in the T-I cells of ovarian follicles. Adult female rats were adminis­tered BPA (0, 0.001, or 0.1 mg/kg BWU/day) or EB (0.001 mg/kg BW/day) for 90 days by gavage. (A) Western blot analysis for P450arom. (B) Densitometric quantification of the P450arom protein level in isolated granulosa cell protein extracts. (C) Immunohistochemical localization of P450arom in the granulosa cell layers of the large antral follicles; e–h are enlargements of the regions marked in a–d (original magnification: a–d, 100×; e–h, 400×; bars = 80 μm in a–d and 30 μm in e–h). (D) Western blot analysis for StAR, P450scc, and 3β-HSD proteins. (E) Densitometric quantification of StAR, P450scc, and 3β-HSD protein levels in residual ovaries. (F) Serum T levels (mean ± SD) measured by ELISA (n = 12); AM represents adult male serum (positive control). (G) Immunohistochemical localization of StAR, P450scc, and 3β-HSD in T-I layers (original magnification: 400×; bar = 30 μm). For B and E, data represent the mean ± SD of at least three independent experiments.*p < 0.05, and **p < 0.01 compared with control (0 mg/kg BW).
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f3: Effect of BPA exposure on P450arom in granulosa cells and StAR, P450scc, and 3β-HSD in the T-I cells of ovarian follicles. Adult female rats were adminis­tered BPA (0, 0.001, or 0.1 mg/kg BWU/day) or EB (0.001 mg/kg BW/day) for 90 days by gavage. (A) Western blot analysis for P450arom. (B) Densitometric quantification of the P450arom protein level in isolated granulosa cell protein extracts. (C) Immunohistochemical localization of P450arom in the granulosa cell layers of the large antral follicles; e–h are enlargements of the regions marked in a–d (original magnification: a–d, 100×; e–h, 400×; bars = 80 μm in a–d and 30 μm in e–h). (D) Western blot analysis for StAR, P450scc, and 3β-HSD proteins. (E) Densitometric quantification of StAR, P450scc, and 3β-HSD protein levels in residual ovaries. (F) Serum T levels (mean ± SD) measured by ELISA (n = 12); AM represents adult male serum (positive control). (G) Immunohistochemical localization of StAR, P450scc, and 3β-HSD in T-I layers (original magnification: 400×; bar = 30 μm). For B and E, data represent the mean ± SD of at least three independent experiments.*p < 0.05, and **p < 0.01 compared with control (0 mg/kg BW).

Mentions: BPA exposure and downregulation of P450arom protein expression in granulosa cells. Ovarian aromatase expressed in granulosa cells facilitates the conversion of E2 from androgens produced in the theca cells of the antral follicles. Thus, we examined whether a change in aromatase expression was associated with E2 synthesis after BPA treatment. Decreased P450arom protein levels were evident in the granulosa cells of animals in both BPA treatment groups (Figure 3A,B). P450arom was predominantly localized in the granulosa cell layers of the large antral (preovulatory) follicles (Figure 3C). P450arom immunoreactivity was remarkably reduced in the BPA- and EB-exposed groups (Figure 3C, b–d and f–h) compared with controls (Figure 3C, a–e).


Bisphenol A exposure during adulthood causes augmentation of follicular atresia and luteal regression by decreasing 17β-estradiol synthesis via downregulation of aromatase in rat ovary.

Lee SG, Kim JY, Chung JY, Kim YJ, Park JE, Oh S, Yoon YD, Yoo KS, Yoo YH, Kim JM - Environ. Health Perspect. (2013)

Effect of BPA exposure on P450arom in granulosa cells and StAR, P450scc, and 3β-HSD in the T-I cells of ovarian follicles. Adult female rats were adminis­tered BPA (0, 0.001, or 0.1 mg/kg BWU/day) or EB (0.001 mg/kg BW/day) for 90 days by gavage. (A) Western blot analysis for P450arom. (B) Densitometric quantification of the P450arom protein level in isolated granulosa cell protein extracts. (C) Immunohistochemical localization of P450arom in the granulosa cell layers of the large antral follicles; e–h are enlargements of the regions marked in a–d (original magnification: a–d, 100×; e–h, 400×; bars = 80 μm in a–d and 30 μm in e–h). (D) Western blot analysis for StAR, P450scc, and 3β-HSD proteins. (E) Densitometric quantification of StAR, P450scc, and 3β-HSD protein levels in residual ovaries. (F) Serum T levels (mean ± SD) measured by ELISA (n = 12); AM represents adult male serum (positive control). (G) Immunohistochemical localization of StAR, P450scc, and 3β-HSD in T-I layers (original magnification: 400×; bar = 30 μm). For B and E, data represent the mean ± SD of at least three independent experiments.*p < 0.05, and **p < 0.01 compared with control (0 mg/kg BW).
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Related In: Results  -  Collection

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f3: Effect of BPA exposure on P450arom in granulosa cells and StAR, P450scc, and 3β-HSD in the T-I cells of ovarian follicles. Adult female rats were adminis­tered BPA (0, 0.001, or 0.1 mg/kg BWU/day) or EB (0.001 mg/kg BW/day) for 90 days by gavage. (A) Western blot analysis for P450arom. (B) Densitometric quantification of the P450arom protein level in isolated granulosa cell protein extracts. (C) Immunohistochemical localization of P450arom in the granulosa cell layers of the large antral follicles; e–h are enlargements of the regions marked in a–d (original magnification: a–d, 100×; e–h, 400×; bars = 80 μm in a–d and 30 μm in e–h). (D) Western blot analysis for StAR, P450scc, and 3β-HSD proteins. (E) Densitometric quantification of StAR, P450scc, and 3β-HSD protein levels in residual ovaries. (F) Serum T levels (mean ± SD) measured by ELISA (n = 12); AM represents adult male serum (positive control). (G) Immunohistochemical localization of StAR, P450scc, and 3β-HSD in T-I layers (original magnification: 400×; bar = 30 μm). For B and E, data represent the mean ± SD of at least three independent experiments.*p < 0.05, and **p < 0.01 compared with control (0 mg/kg BW).
Mentions: BPA exposure and downregulation of P450arom protein expression in granulosa cells. Ovarian aromatase expressed in granulosa cells facilitates the conversion of E2 from androgens produced in the theca cells of the antral follicles. Thus, we examined whether a change in aromatase expression was associated with E2 synthesis after BPA treatment. Decreased P450arom protein levels were evident in the granulosa cells of animals in both BPA treatment groups (Figure 3A,B). P450arom was predominantly localized in the granulosa cell layers of the large antral (preovulatory) follicles (Figure 3C). P450arom immunoreactivity was remarkably reduced in the BPA- and EB-exposed groups (Figure 3C, b–d and f–h) compared with controls (Figure 3C, a–e).

Bottom Line: Exposure to BPA significantly decreased E2 serum concentration, which was accompanied by augmented follicular atresia and luteal regression via increase of caspase-3-associated apoptosis in ovarian cells.However, P450scc and 3β-HSD protein levels remained unchanged.The steroidogenic proteins StAR and P450arom appear to be targeted by BPA.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan, Korea.

ABSTRACT

Background: Bisphenol A (BPA) has been detected in human body fluids, such as serum and ovarian follicular fluids. Several reports indicated that BPA exposure is associated with the occurrence of several female reproductive diseases resulting from the disruption of steroid hormone biosynthesis in the adult ovary.

Objective: We hypothesized that long-term exposure to low concentrations of BPA disrupts 17β-estradiol (E2) production in granulosa cells via an alteration of steroidogenic proteins in ovarian cells.

Methods: Adult female rats received BPA for 90 days by daily gavage at doses of 0, 0.001, or 0.1 mg/kg body weight. We determined serum levels of E2, testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). We also analyzed the expressions of steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase isomerase (3β-HSD), and aromatase cytochrome P450 (P450arom) in the ovary.

Results: Exposure to BPA significantly decreased E2 serum concentration, which was accompanied by augmented follicular atresia and luteal regression via increase of caspase-3-associated apoptosis in ovarian cells. After BPA exposure, P450arom and StAR protein levels were significantly decreased in granulosa cells and theca-interstitial (T-I) cells, respectively. However, P450scc and 3β-HSD protein levels remained unchanged. The increase in LH levels appeared to be associated with the decreased synthesis of T in T-I cells after BPA exposure via homeostatic positive feedback regulation.

Conclusions: BPA exposure during adulthood can disturb the maintenance of normal ovarian functions by reducing E2. The steroidogenic proteins StAR and P450arom appear to be targeted by BPA.

Show MeSH
Related in: MedlinePlus