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reduction in ovarian granulosa cells, Aromatase (Cyp19a1) leads to Reduction, 17beta-estradiol synthesis by ovarian granulosa cells
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female||adjacent||Moderate||Elise Grignard (send email)||Open for citation & comment||EAGMST Under Review|
Life Stage Applicability
Key Event Relationship Description
Aromatase is the cytochrome P450 enzyme complex responsible for the conversion of androgens to estrogens during steroidogenesis [reviewed by (Simpson et al., 1994)], which is a key reaction in the sex differentiation in vertebrates. Reduction in level of aromatase or in the catalytic activity of the aromatase itself will reduce the levels of estrogens in tissues and dramatically disrupt estrogen (E2) hormone action.
Evidence Supporting this KER
Aromatase in the specialized cells of the ovary, hypothalamus, and placenta clearly serves crucial role in reproduction for mammalian and other vertebrates by converting the androgens to estrogens. Therefore, the coordinated and cell-specific expression of the aromatase (Cyp19a1) gene in the ovary plays a key role in the 17beta-estradiol (E2) synthesis. Within the ovary, aromatase expression and activity is primarily localized in the granulosa cells (reviewed in (Havelock, Rainey, & Carr, 2004). C-19 androgens diffuse from the theca cells into granulosa cells where aromatase can catalyze their conversion to C-18 estrogens. Therefore, inhibition, decrease of level or activity of ovarian aromatase can generally be assumed to directly impact E2 synthesis by the granulosa cells.
Uncertainties and Inconsistencies
Upstream events An upstream event has been postulated to involve PPARγ activation, however the studies confirming its role in the reduction of aromatase levels are incomplete. The mechanisms involving Peroxisome Proliferator Activated receptor γ activation leading to aromatase (Cyp19a1) reduction relating to the pathway are described in greater detail in the page Peroxisome Proliferator Activated receptor γ activation indirectly leads to aromatase (Cyp19a1) reduction .
Availability or reduced aromatase levels
Studies by Davis et al showed that MEHP impacts on availability (degradation) of aromatase as the decrease in E2 production is evident after the treatment with transcription and translation blockers (actinomycin D or cycloheximide). MEHP was further decreased E2 production independently of the presence of inhibitors pointing out at mechanisms of degradation rather than aromatase synthesis (Davis et al., 1994). MEHP can indirectly impact on aromatase rates by decreasing necessary cofactors (availability) or activation of aromatase inhibitors. Treinin et al showed in vitro dose dependent inhibition of progesterone production by MEHP in granulosa cells and reduced FSH-stimulated cAMP accumulation in granulosa cells implicating a direct or indirect effect of MEHP on FSH receptor (Treinen, Dodson, & Heindel, 1990). Similar effects of cAMP accumulation were seen in Sertoli cells (Lloyd & Foster, 1988), (Heindel & Chapin, 1989), (Heindel & Powell, 1992). Since granulosa and Sertoli cells share several structural and functional characteristics this mechanism is plausible. Study by Ma et al showed that inhaled DEHP (5 and 25 mg/m3) increased levels of LH and E2 in serum of prepubertal rats, and it increased ovarian Cyp19a1 expression (Ma et al., 2006), which is in disagreement with the key event relationship. This difference might be due to measurements of hormones during different phases of the estrous cycle, alterations in the experimental approaches used (in vivo versus in vitro) as well as exposure routes and doses given.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
See table 1.
Davis, B. J., Weaver, R., Gaines, L. J., & Heindel, J. J. (1994). Mono-(2-ethylhexyl) phthalate suppresses estradiol production independent of FSH-cAMP stimulation in rat granulosa cells. Toxicology and Applied Pharmacology, 128(2), 224–8. doi:10.1006/taap.1994.1201
Gupta, R. K., Singh, J. M., Leslie, T. C., Meachum, S., Flaws, J. a, & Yao, H. H.-C. (2010). Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro. Toxicology and Applied Pharmacology, 242(2), 224–30. doi:10.1016/j.taap.2009.10.011
Havelock, J. C., Rainey, W. E., & Carr, B. R. (2004). Ovarian granulosa cell lines. Molecular and Cellular Endocrinology, 228(1-2), 67–78. doi:10.1016/j.mce.2004.04.018
Heindel, J. J., & Chapin, R. E. (1989). Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat Sertoli cell cultures. Toxicology and Applied Pharmacology, 97(2), 377–85.
Heindel, J. J., & Powell, C. J. (1992). Phthalate ester effects on rat Sertoli cell function in vitro: effects of phthalate side chain and age of animal. Toxicology and Applied Pharmacology, 115(1), 116–23.
Kwintkiewicz, J., Nishi, Y., Yanase, T., & Giudice, L. C. (2010). Peroxisome proliferator-activated receptor-gamma mediates bisphenol A inhibition of FSH-stimulated IGF-1, aromatase, and estradiol in human granulosa cells. Environmental Health Perspectives, 118(3), 400–6. doi:10.1289/ehp.0901161
Lloyd, S. C., & Foster, P. M. (1988). Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells. Toxicology and Applied Pharmacology, 95(3), 484–9.
Lovekamp, T. N., & Davis, B. J. (2001). Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicology and Applied Pharmacology, 172(3), 217–24. doi:10.1006/taap.2001.9156
Ma, M., Kondo, T., Ban, S., Umemura, T., Kurahashi, N., Takeda, M., & Kishi, R. (2006). Exposure of prepubertal female rats to inhaled di(2-ethylhexyl)phthalate affects the onset of puberty and postpubertal reproductive functions. Toxicological Sciences : An Official Journal of the Society of Toxicology, 93(1), 164–71. doi:10.1093/toxsci/kfl036
Reinsberg, J., Wegener-Toper, P., van der Ven, K., van der Ven, H., & Klingmueller, D. (2009). Effect of mono-(2-ethylhexyl) phthalate on steroid production of human granulosa cells. Toxicology and Applied Pharmacology, 239(1), 116–23. doi:10.1016/j.taap.2009.05.022
Simpson, E. R., Mahendroo, M. S., Means, G. D., Kilgore, M. W., Hinshelwood, M. M., Graham-Lorence, S., … Michael, M. D. (1994). Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine Reviews, 15(3), 342–55. doi:10.1210/edrv-15-3-342
Treinen, K. A., Dodson, W. C., & Heindel, J. J. (1990). Inhibition of FSH-stimulated cAMP accumulation and progesterone production by mono(2-ethylhexyl) phthalate in rat granulosa cell cultures. Toxicology and Applied Pharmacology, 106(2), 334–40.
Xu, C., Chen, J.-A., Qiu, Z., Zhao, Q., Luo, J., Yang, L., … Shu, W. (2010). Ovotoxicity and PPAR-mediated aromatase downregulation in female Sprague-Dawley rats following combined oral exposure to benzo[a]pyrene and di-(2-ethylhexyl) phthalate. Toxicology Letters, 199(3), 323–32. doi:10.1016/j.toxlet.2010.09.015