Initial uterine alterations caused by developmental exposure to tamoxifen

Poulet, Frederique M.; Roessler, Michele L.; Vancutsem, Paul M.

doi:10.1016/s0890-6238(97)00065-8

Cited by 17 publications

(10 citation statements)

References 34 publications

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“…Although increased PRL release is a well characterized effect of estrogens, serum PRL levels in adult mice, neonatally treated with DES, were unchanged (27,28). These reports agree with our observation that DES, at a dose similar to that used by others (27)(28)(29)(30), causes only a transient rise in serum PRL levels in prepubertal male and female rats. Despite having a 10,000-fold higher binding affinity to the ER than the xenoestrogens, DES had only modest effects on receptor expression in the neuroendocrine system.…”

Section: Discussionsupporting

confidence: 92%

Exposure of Newborn Male and Female Rats to Environmental Estrogens: Delayed and Sustained Hyperprolactinemia and Alterations in Estrogen Receptor Expression**This work was supported by NIH Grants ES-09555, ES-10154, and CA-80920; March of Dimes Grant 6-FY98–0159; and a grant from the Pardee Foundation. Preliminary results of this investigation were presented at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, June 2000.

2000

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Environmental estrogens (xenoestrogens) are synthetic compounds that are abundant in the environment and mimic natural estrogens. The estrogenicity of two such compounds, bisphenol A (BPA) and octylphenol (OP), during development of the neuroendocrine system was investigated. The objective was to compare the effects of neonatal exposure to BPA, OP, and diethylstilbestrol (DES), a potent synthetic estrogen, on prepubertal serum PRL levels and estrogen receptor (ER) expression in the anterior pituitary and medial basal hypothalamus. Receptor expression in the uterus and prostate, two peripheral estrogen-responsive tissues, was also examined. Newborn male and female Fischer 344 rats were sc injected on days 1-5 after birth with corn oil (control), BPA and OP (100 or 500 g/day), or DES (5 g/day). Rats were bled on days 15, 20, and 25 and on the day of death (day 30), and serum PRL was analyzed by RIA. Relative expressions of ER␣ and ER␤ were determined by RT-PCR. BPA and OP induced delayed, but progressive, increases in serum PRL levels, up to 3-fold above control levels, in both males and females. The low dose of either compound was equally or more effective as the high dose in eliciting and sustaining elevated serum PRL levels, namely hyperprolactinemia. In contrast, the DES treatment resulted in a transient rise in serum PRL levels. BPA, OP, and, to a lesser extent, DES increased the expression of both ER␣ and ER␤ in the anterior pituitary of males, but not females, whereas the hypothalamic ERs were less responsive to these compounds. DES treatment caused downregulation of ER␣ expression in the uterus and up-regulation of ER␤ in the prostate, whereas BPA or OP was without effect. In conclusion, exposure of newborn rats of either sex to environmental estrogens results in delayed and sustained hyperprolactinemia and differential alterations in ER expression in the hypothalamus and pituitary. DES appears to target the lower reproductive tract more effectively than the neuroendocrine system. (Endocrinology 141: [4512][4513][4514][4515][4516][4517] 2000) E NVIRONMENTAL estrogens (xenoestrogens) are a diverse group of synthetic compounds that are abundant in the environment and mimic the action of estrogens. Two such compounds, bisphenol A (BPA) and octylphenol (OP), were the focus of this investigation (Fig. 1). BPA is composed of two unsaturated phenolic rings that resemble diethylstilbestrol (DES). BPA is a monomer of polycarbonate plastics and a constituent of epoxy and polystyrene resins used in the food packaging industry and dentistry (1, 2). The polymer bonds can hydrolyze at high temperature and release BPA. Detectable amounts of BPA were found in food cans (3), microwaved pizzas (4), and human saliva after treatment with dental sealants (5). OP, comprised of a single phenolic ring (Fig. 1), is a constituent of alkylphenol polyethoxylates that are used as surfactants in detergents, paints, and herbicides. Alkylphenols are degraded in treatment plants to form stable products, OP and nonylphenol, whic...

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Section: Discussionsupporting

confidence: 92%

Exposure of Newborn Male and Female Rats to Environmental Estrogens: Delayed and Sustained Hyperprolactinemia and Alterations in Estrogen Receptor Expression**This work was supported by NIH Grants ES-09555, ES-10154, and CA-80920; March of Dimes Grant 6-FY98–0159; and a grant from the Pardee Foundation. Preliminary results of this investigation were presented at the 82nd Annual Meeting of The Endocrine Society, Toronto, Canada, June 2000.

2000

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“…In favour of this hypothesis are the following facts: (1) perinatal treatment of male rats with tamoxifen caused reproductive tract lesions and sexual behaviour deficits similar to those induced by diethylstilboestrol (DES; a synthetic compound with oestrogenic activity) , (2) tamoxifen administered neonatally showed uterotrophic action similar to DES (Poulet et al 1997), (3) the effects of raloxifene and oestradiol given neonatally to female and male rats were similar (Pinilla et al 2001a), (4) raloxifene showed, in adult ovariectomized females, an oestrogen-like action evidenced by the reduction in LH secretion and the increase of prolactin release (Pinilla et al 2001b) and (5) raloxifene was unable to block the effects of oestradiol and testosterone given neonatally.…”

Section: Discussionmentioning

confidence: 99%

Comparative effects of testosterone propionate, oestradiol benzoate, ICI 182,780, tamoxifen and raloxifene on hypothalamic differentiation in the female rat

Pinilla¹,

Barreiro²,

Gonzalez³

et al. 2002

Journal of Endocrinology

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Hypothalamic differentiation in the female rat during the neonatal period is critically dependent on the steroid milieu, as permanent changes in reproductive function are observed after administration of oestradiol and testosterone during such a critical stage. Selective oestrogen modulators (SERMs) constitute a family of drugs that, depending on the tissue, are able to exert oestrogenic or antioestrogenic actions. The present experiments were conducted to analyse whether the SERMs, tamoxifen and raloxifene, can cause oestrogenic actions during the hypothalamic differentiation period.Postnatal female rats were injected between days 1 and 5 with 100 µg/day tamoxifen, raloxifene or ICI 182,780 (a pure antioestrogen). Other groups of animals were injected on day 1 of age with 100 µg oestradiol benzoate (OeB) or 1·25 mg testosterone propionate (TP) alone or in combination with raloxifene (500 µg/day between days 1 and 5). In all experimental groups, the age, body weight and concentrations of serum gonadotrophins at vaginal opening were recorded, whereas vaginal cyclicity and the negative and positive feedback between oestradiol and LH were monitored in adulthood.The results obtained confirmed the ability of high doses of OeB or TP to alter the normal differentiation of the brain permanently. They also reinforced the hypothesis that oestrogens are also necessary for normal brain differentiation in female rats because administration of a pure antioestrogen, such as ICI 182,780 permanently altered the function of the reproductive axis. In addition, our data provided evidence for different actions of the two SERMs under analysis (raloxifene and tamoxifen) upon peripheral targets, as raloxifene advanced vaginal opening whereas tamoxifen did not. In contrast, their actions on brain differentiation appeared similar and analogous to those obtained after neonatal administration of oestradiol, as evidenced by vaginal acyclicity, ovarian atrophy, sterility and abolition of negative and positive feedback between oestradiol and LH, thus suggesting an oestrogenic action of these SERMs on hypothalamic differentiation. Moreover, the oestrogenic activity of raloxifene was supported by its inability to block the effects of OeB and TP administered neonatally.In conclusion, the present results indicated that the SERMs, tamoxifen and raloxifene, exert an oestrogen-like effect upon hypothalamic differentiation of the neonatal female rat.

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“…At the same time, they act as estrogen agonists in the bone and cardiovascular system, where they counteract osteoporosis and coronary syndromes. Finally, in the uterus, tamoxifen shows a similar activity to estrogen and for this reason is associated to a higher risk of endometrial carcinoma [56,59].…”

Section: Phytoestrogensmentioning

confidence: 99%

Estrogens, phytoestrogens and colorectal neoproliferative lesions

et al. 2008

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Epidemiological and experimental studies suggest a protective role of estrogens against colorectal cancer. This effect seems to be mediated by their binding to estrogen receptor beta (ER-beta), one of the two estrogen receptors with high affinity for these hormones. Very recently, the demonstration of an involvement of ER-beta in the development of adenomatous polyps of the colon has also been documented, suggesting the use of selective ER-beta agonists in primary colorectal cancer prevention. Phytoestrogens are plant-derived compounds that structurally and functionally act as estrogen-agonists in mammals. They are characterized by a higher binding affinity to ER-beta as compared to estrogen receptor alpha (ER-alpha), the other estrogen receptor subtype. These biological characteristics explain why the administration of phytoestrogens does not produce the classical side effects associated to estrogen administration (cerebro- and cardio-vascular accidents, higher incidence of endometrial and breast cancer) and makes these substances ideal candidates for the prevention of colorectal cancer.

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Initial uterine alterations caused by developmental exposure to tamoxifen

Cited by 17 publications

References 34 publications

Comparative effects of testosterone propionate, oestradiol benzoate, ICI 182,780, tamoxifen and raloxifene on hypothalamic differentiation in the female rat

Estrogens, phytoestrogens and colorectal neoproliferative lesions

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