Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses

Jefferson, Wendy N.; Padilla-Banks, Elizabeth; Clark, George C.; Newbold, Retha R.

doi:10.1016/s1570-0232(02)00493-2

Cited by 127 publications

(93 citation statements)

References 30 publications

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“…DES is known to have more estrogenic activity than E in vitro and in vivo [42,43]. In accordance with this, the negative effects of E in our study, administered in the same doses as DES, were less pronounced and showed a clear dose-dependent pattern for most of the parameters studied.…”

Section: Discussionsupporting

confidence: 90%

Xenoestrogens diethylstilbestrol and zearalenone negatively influence pubertal rat's testis.

Filipiak

Walczak-Jędrzejowska²,

Oszukowska³

et al. 2010

Folia Histochem Cytobiol.

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Abstract:The aim of this study was to assess the impact of xenoestrogens: diethylstilbestrol (DES) and zearalenone (ZEA) on rat's pubertal testis and to compare it with the effect of natural estrogen -17β-estradiol (E). Male Wistar rats were daily, subcutaneously injected at 5 th -15 th postnatal days (p.d.) with E (1.25 or 12.5 μg) or DES (1.25 or 12.5 μg) or ZEA (4 or 40 μg) or vehicle. At 16 th p.d. testes were dissected, weighted, and paraffin embedded. Following parameters were assessed: diameter and length of seminiferous tubule, numbers of spermatogonia A+intermediate+B (A/In/B), preleptotene spermatocytes (PL), leptotene+zygotene+pachytene spermatocytes (L/Z/PA) and Sertoli cells per testis. Testes weight, seminiferous tubule diameter and length were decreased by both doses of E, DES and ZEA. DES effect was the strongest, but its influence on testis weight and seminiferous tubule length, on the contrary to E and ZEA, was not dose-dependent. Similarly, DES in both doses had the most severe negative impact on the number of germ and Sertoli cells. The negative influence of E on germ cells was less pronounced. The negative effect of ZEA was seen only after administration of the higher dose on spermatogonia number, while DES and E decreased A/In/B number more evidently. Sertoli cell number were decreased after both doses of E. ZEA40 decreased Sertoli cell number while ZEA4 had no effect. Conclusion: exposure of prepubertal male rat to DES has the strongest detrimental effect on the developing testis in comparison to E and ZEA. Both, E and DES, decreased number of germ and Sertoli cells, diminished seminiferous tubule diameter, length and testis weight. ZEA had much more weaker effect than the potent estrogens.

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Section: Discussionsupporting

confidence: 90%

Xenoestrogens diethylstilbestrol and zearalenone negatively influence pubertal rat's testis.

Filipiak

Walczak-Jędrzejowska²,

Oszukowska³

et al. 2010

Folia Histochem Cytobiol.

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“…Furthermore, 8-PN and IX were also evaluated since 8-PN is the major active phytoestrogen in H. lupulus [16,17,20,21], and IX can be metabolized to 8-PN [22]. The major phytoestrogens in T. pratense, daidzein and genistein, and their metabolic precursors, formononetin and biochanin A, were not evaluated since there is already a large body of data on these compounds [36,37], and the primary focus was on H. lupulus. Uterus weight was used as the primary outcome measure and body weight was one of the secondary outcome measures.…”

Section: Discussionmentioning

confidence: 99%

In vivo estrogenic comparisons of Trifolium pratense (red clover) Humulus lupulus (hops), and the pure compounds isoxanthohumol and 8-prenylnaringenin

Overk

Guo

Chadwick

et al. 2008

Chemico-Biological Interactions

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The lack of a safe and reliable alternative to hormone therapy (HT) for treating menopausal symptoms underscores the need for alternative therapies. OBJECTIVE: The purpose of this study was to assess the in vivo estrogenic effects of the botanical dietary supplements Trifolium pratense (red clover) and Humulus lupulus (hops), and two compounds obtained from H. lupulus, isoxanthohumol and 8-prenylnaringenin (8-PN) using the ovariectomized uterotrophic adult rat model. A H. lupulus extract and a 30% isoflavone extract of T. pratense were tested at three escalating doses as was one dose of isoxanthohumol for 21 days. 8-Prenylnaringenin, the major estrogen in H. lupulus, was also tested at three relevant escalating doses. In order to determine the in vivo metabolism of 8-PN, the major Phase I and Phase II metabolites were also identified. The primary outcome measure, uterus weight gain, indicated that H. lupulus and T. pratense did not have an estrogenic effect on the uterus, and none of the secondary outcome measures were positive. In contrast, there was a clear dose response when 8-PN was evaluated where the middle and high doses of 8-PN were active. 8-Prenylnaringenin in rat plasma, liver, and mammary gland was measured and the major Phase I and Phase II 8-PN metabolites were detected. Our findings suggest that while both the H. lupulus and T. pratense extracts do not have an effect on the rat uterus, 8-PN at equivalent doses to those previously used in humans did have an effect, and may therefore have a deleterious effect in women. IntroductionSymptoms associated with menopause such as insomnia, loss of libido, vaginal atrophy, depression, and hot flashes can greatly affect the quality of life for women. Many women have used hormone therapy (HT) to alleviate menopausal symptoms; however, with the publication The strobiles of Humulus lupulus L. (Cannabaceae) (hops) are primarily used to flavor beer, and have been studied since 1953 for a potential estrogenic mechanism of action [13][14][15]. In the past, the flavonoids 8-PN and 6-PN, and the chalcone, isoxanthohumol (IX), have been isolated and reported to be estrogenic in vitro and/or in vivo [16,17]. The most potent estrogen in H. lupulus is 8-PN, which is in actuality an artifact formed through isomerization of the precursor chalcone, desmethylxanthohumol [18,19]. 8-Prenylnaringenin has been shown in a variety of in vitro assays to be estrogenic in the nanomolar range [16,17,20,21]. It can also be formed from precursors such as IX, and xanthohumol (XH), through metabolism [22].In previous metabolic studies, it has been shown that human liver microsomes convert 8-PN to 12 metabolites [22]. Among them, are the most abundant monooxygenated metabolites (Figure 1). The estrogenicities of the 8-PN alcohols have been previously determined [23] and were found to be ∼10 fold less estrogenic than 8-PN. Phase II metabolites of 8-PN, including glucuronides and sulfate conjugates, have been identified in incubations with human Caco-2 cells and human hepatocytes [2...

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“…These include determination of uterine epithelial cell height, uterine gland formation, cell proliferation, rat uterine gene expression e.g. complement C3, progesterone receptor, clusterin, and the production of the estrogen-inducible protein, lactoferrin in the uterine epithelial cells (Ashby, 2001;Diel et al, 2001;Newbold et al, 2001;Jefferson et al, 2002;Diel et al, 2004).…”

Section: Testing Estrogenicity Testing Estrogenicity Testing Estrogenmentioning

confidence: 99%

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

Saarinen

Bingham²,

Lorenzetti

et al. 2006

Genes Nutr

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Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses

Cited by 127 publications

References 30 publications

Xenoestrogens diethylstilbestrol and zearalenone negatively influence pubertal rat's testis.

Xenoestrogens diethylstilbestrol and zearalenone negatively influence pubertal rat's testis.

In vivo estrogenic comparisons of Trifolium pratense (red clover) Humulus lupulus (hops), and the pure compounds isoxanthohumol and 8-prenylnaringenin

Tools to evaluate estrogenic potency of dietary phytoestrogens:A consensus paper from the EU Thematic Network “Phytohealth” (QLKI-2002-2453)

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