API

Relationship: 392

Title

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Reduction, Plasma 17beta-estradiol concentrations leads to irregularities, ovarian cycle

Upstream event

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Reduction, Plasma 17beta-estradiol concentrations

Downstream event

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irregularities, ovarian cycle

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
Aromatase (Cyp19a1) reduction leading to impaired fertility in adult female directly leads to Strong

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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The development and the function of the female reproductive tract depends upon hormone concentrations and balance. Changes in this fine-tuned hormonal machinery may result in reproductive system dysfunction (e.g. menstrual cycle irregularities, impaired fertility, endometriosis, polycystic ovarian syndrome). Ovarian estrogen is the major component of negative and positive feedback for pituitary release of gonadotrophic hormones; therefore abnormal alterations in the estradiol levels result in irregularities of the ovarian cycle.

Weight of Evidence

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Biological Plausibility

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Estrogens are crucial for female and male fertility, as proved by the severe reproductive defects observed when their synthesis (Simpson, 2004), (Schomberg et al., 1999) are blocked. As a secreted hormone, estradiol modulates the structure and function of female reproductive tissues, such as the uterus and oviduct. Estradiol is also one of the principal determinants of pituitary neuron functioning and is critical in enabling these cells to exhibit fluctuating patterns of biosynthetic and secretory activity and to generate the preovulatory surge of luteinising hormone (LH) (Hillier, 1985). Estradiol also contributes to cyclical variations in sexual female behaviour. Suppression of estradiol levels results in increased serum follicle stimulating hormone (FSH) levels and an absence of LH surges necessary for ovulation (Everett, 1961), (Davis, Maronpot, & Heindel, 1994) and changes the length of the cycle (Eldridge et al., 1994).

Empirical Support for Linkage

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A disruption of cycling caused by xenobiotic treatment can induce changes of length of the phases or cause an irregular pattern with cycles of extended duration and/or impact on ovulation. Measurements of serum estradiol reflect primarily the activity of the ovaries. As such, they are useful in the detection of baseline estrogen in irregularities of ovarian cycle. Suppressed levels of estradiol were found to impact on ovulation (Davis et al., 1994) and cycle duration (Hirosawa, Yano, Suzuki, & Sakamoto, 2006), (Eldridge et al., 1994), (Davis et al., 1994). Table 1 summarises common classes of chemicals shown to cause cycle irregularities through modulation of the hormonal balance.

Compound class

species

KE: Reduced E2


KE: Ovarian cycle irregularities

Reference

Phthalates (DEHP)


rat

Reduced serum E2

prolonged the estrous cycle, anovulation (3000 mg/kg/day)

(Davis et al., 1994)

Phthalates (DEHP)

rat

Reduced serum E2; FSH, pitutiary FSH, LH

irregular estrous cycles, prolongation of the cycle

(Takai et al., 2009)

Phthalates (DEHP)

rat

decreased E2 levels in estrus increased levels in diestrus

alters the estrous cycle

(Laskey & Berman, 1993)

Phthalates (DEHP)

rat

Reduced serum E2; FSH, pituitary FSH and LH

continuous diestrus stage

(Hirosawa et al., 2006)

Chlorotriazines (trazine)

rat

reduced plasma E2 by 63% and 88% at does 100 or 300 mg/kg ,respectively)

cycle lengthening, and increase in days spent in estrus and decrease in proestrus (100 or 300 mg/kg)

(Eldridge et al., 1994)

Phenols (4-tert-octylphenol)

rat

Progesterone elevated

Decreased number of cycles, diestrus was extended

(Laws, 2000)

Phthalates (DEHP)

sheep

Progesterone elevated

Increased mean cycle length, Short cycles (dose-dependent)

(Herreros et al., 2013)

Phthalates (DEHP)

rat


Deficit in growing follicles and corpora lutea

(Schilling, K., Deckardt. K., Gembardt, Chr., and Hildebrand, 1999)

dioxins

rat


Prolonged diestrus

(Li, Johnson, & Rozman, 1995);



Table 1 Summary of the empirical evidence supporting KER. Estradiol (E2), luteinising hormone (LH) and follicle stimulating hormone (FSH).

Uncertainties or Inconsistencies

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The impact on the ovarian cycle may result from defect in hypothalamic-pituitary-gonadal (HPG) axis signalling, other than by alteration of estradiol level. Table 1 shows some chemicals which impact on other hormones and cause irregularities of ovarian cycle.

Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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See Table 1.

References

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Davis, B J, R R Maronpot, and J J Heindel. 1994. “Di-(2-Ethylhexyl) Phthalate Suppresses Estradiol and Ovulation in Cycling Rats.” Toxicology and Applied Pharmacology 128 (2) (October): 216–23. doi:10.1006/taap.1994.1200.

Eldridge, J C, D G Fleenor-Heyser, P C Extrom, L T Wetzel, C B Breckenridge, J H Gillis, L G Luempert, and J T Stevens. 1994. “Short-Term Effects of Chlorotriazines on Estrus in Female Sprague-Dawley and Fischer 344 Rats.” Journal of Toxicology and Environmental Health 43 (2) (October): 155–67. doi:10.1080/15287399409531912.

Everett, J. W. 1961. “The Mammalian Female Reproductive Cycle and Its Controlling Mechanisms.” Sex and Internal Secretions I. Herreros, Maria a, Antonio Gonzalez-Bulnes, Silvia Iñigo-Nuñez, Ignacio Contreras-Solis, Jose M Ros, and Teresa Encinas. 2013. “Toxicokinetics of di(2-Ethylhexyl) Phthalate (DEHP) and Its Effects on Luteal Function in Sheep.” Reproductive Biology 13 (1) (March): 66–74. doi:10.1016/j.repbio.2013.01.177.

Hillier, S G. 1985. “Sex Steroid Metabolism and Follicular Development in the Ovary.” Oxford Reviews of Reproductive Biology 7 (January): 168–222.

Hirosawa, Narumi, Kazuyuki Yano, Yuko Suzuki, and Yasushi Sakamoto. 2006. “Endocrine Disrupting Effect of Di-(2-Ethylhexyl)phthalate on Female Rats and Proteome Analyses of Their Pituitaries.” Proteomics 6 (3) (February): 958–71. doi:10.1002/pmic.200401344.

Laskey, J.W., and E. Berman. 1993. “Steroidogenic Assessment Using Ovary Culture in Cycling Rats: Effects of Bis (2-Diethylhexyl) Phthalate on Ovarian Steroid Production.” Reproductive Toxicology 7 (1) (January): 25–33. doi:10.1016/0890-6238(93)90006-S. Laws, S. C. 2000. “Estrogenic Activity of Octylphenol, Nonylphenol, Bisphenol A and Methoxychlor in Rats.” Toxicological Sciences 54 (1) (March 1): 154–167. doi:10.1093/toxsci/54.1.154.

Li, X, D C Johnson, and K K Rozman. 1995. “Effects of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) on Estrous Cyclicity and Ovulation in Female Sprague-Dawley Rats.” Toxicology Letters 78 (3) (August): 219–22.

Schilling, K., Deckardt. K., Gembardt, Chr., and Hildebrand, B. 1999. “Di-2-Ethylhexyl Phthalate – Two-Generation Reproduction Toxicity Range-Finding Study in Wistar Rats. Continuos Dietary Administration.”

Schomberg, D W, J F Couse, A Mukherjee, D B Lubahn, M Sar, K E Mayo, and K S Korach. 1999. “Targeted Disruption of the Estrogen Receptor-Alpha Gene in Female Mice: Characterization of Ovarian Responses and Phenotype in the Adult.” Endocrinology 140 (6) (June): 2733–44. doi:10.1210/endo.140.6.6823.

Simpson, Evan R. 2004. “Models of Aromatase Insufficiency.” Seminars in Reproductive Medicine 22 (1) (February): 25–30. doi:10.1055/s-2004-823024.

Takai, Ryo, Shuji Hayashi, Junpei Kiyokawa, Yoshika Iwata, Saori Matsuo, Masami Suzuki, Keiji Mizoguchi, Shuichi Chiba, and Toshiaki Deki. 2009. “Collaborative Work on Evaluation of Ovarian Toxicity. 10) Two- or Four-Week Repeated Dose Studies and Fertility Study of Di-(2-Ethylhexyl) Phthalate (DEHP) in Female Rats.” The Journal of Toxicological Sciences 34 Suppl 1 (I) (January): SP111–9.