© 2000 by The Society for Integrative and Comparative Biology
Endocrine Disruption and Developmental Abnormalities of Female Reproduction1
1 Center for Integrative Bioscience, Okazaki National Research Institutes, 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Japan, Department of Biology and Graduate School of Integrated Science, Yokohama City University, Kanazawa-ku, Yokohama 236-0027, Japan, CREST, Japan Science and Technology Corporation
2 Department of Biology and Graduate School of Integrated Science, Yokohama City University, Kanazawa-ku, Yokohama 236-0027, Japan
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SYNOPSIS |
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 SYNOPSIS INTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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The developing organism is particularly sensitive to exposure to estrogenic chemicals during a critical period in the induction of longterm changes in female reproductive organs, and persistent molecular alterations induced by the perinatal estrogenic agents. The perinatal mouse model can be utilized as an indicator of possible longterm consequences of exposure to exogenous estrogenic compounds including environmental endocrine disruptors. Attention should be paid to abnormalities in female genital organs exposed to estrogenic endocrine disruptors during fetal and early postnatal development in mammals including humans.
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INTRODUCTION |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Perinatal sex-hormone exposure has been found to induce lesions in the vagina, cervix and uterus in female mice (Dunn and Green, 1963
; Takasugi and Bern, 1964; Iguchi and Takasugi, 1987). The possible relevance of the mouse findings to the development of cancer in humans was emphasized by these investigators. Herbst et al. demonstrated a close correlation between the occurrence of vaginal clear cell adenocarcinoma in young women and early intrauterine exposure to diethylstilbestrol (DES) in the early seventy's (see Herbst and Bern, 1981). Many chemicals released into the environment possibly disrupt the endocrine system in wildlife and humans, and some of these have estrogenic activity as determined by binding to the estrogen receptor (ER) (Colborn and Clement, 1992).Mice exposed perinatally to estrogens provide a model for exploration of the consequences of DES exposure in the human, because mouse genital tract development at birth is similar to that of the human fetus at the end of the first trimester. The neonatal mouse model has been utilized especially to demonstrate the long-term effects of early sex hormone exposure on the female reproductive tract (see Takasugi, 1976; Herbst and Bern, 1981; Bern, 1992; Iguchi, 1992; Iguchi and Bern, 1996). Neonatal treatment of female mice with estrogens induces various abnormalities in the reproductive tract; ovary-independent cervicovaginal keratinization, adenosis and tumors; uterine hypoplasia, epithelial metaplasia and tumors; oviductal tumors; and polyovular follicles and polyfollicular ovaries. The growth response of neonatally DES-exposed reproductive organs to estrogen is reduced, as are ER levels (Bern et al., 1987), epidermal growth factor (EGF) receptor levels (Iguchi et al., 1993), along with other hormone receptor levels (see Bern, 1992). The utility of the neonatal mouse model in indicating permanent, longterm changes, both overt and cryptic, in a variety of structures, both reproductive and nonreproductive, is emphasized, with particular attention herein to newer information of estrogens on ER expression, oncogene and Hox and Wnt gene expression, ovarian abnormalities, fertilizability, and skeletal and muscular tissues. |
HYPOTHALAMO-HYPOPHYSIAL AXIS |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Sex hormones play a crucial role in reproductive neuroendocrine functions. Estrogen or aromatizable androgen plays a significant role in modulating neuronal development and neuronal circuit formation during the perinatal period (see Gorski, 1979
; McEwen, 1991). Aromatization of androgen to estrogen occurs in the brain. Perinatal sex hormone exposure induces permanent sexual dimorphism such as nuclear volume, neuronal number, neuronal membrane organization, synaptic formation and neuronal connectivity in the hypothalamus (see Matsumoto et al., 2000). Sexually dimorphic neuroendocrine and behavioral functions such as regulatory mechanisms of gonadotropin secretion and sexual behavior are considered to be organized by exposure of developing brain to sex steroids during the perinatal period (Gorski, 1979). These functional sexual differences are correlated with the sexual differences in neuronal structures of the hypothalmus. Short-term administration of sex hormones including DES to rodents during a critical period results in persistent changes in the hypothalmo-hypophysio-gonadal system (infertility) and in reproductive tracts (estrogen-independent vaginal proliferation). Two different mechanisms will result in the common endpoint of persistent vaginal cornification: (1) ovary (estrogen)-dependent changes involving the hypothalamo-hypophysial complex, and (2) ovary-independent changes directly affecting the vagina, leading to a permanently cornified epithelial lining even in the total absence of endogenous estrogen (see Takasugi, 1976; Bern and Talamantes, 1981). Mice in this latter category are also affected at the hypothalamic level. However, neonatal treatment of female mice with non-aromatizable androgen, 5
-dihydrotestosterone, induces ovary-independent vaginal changes without affecting hypothalamo-hypophysial-gonadal axis, exhibiting normal ovulation (see Iguchi, 1992). More precise studies are needed on neuroendocrine and behavioral changes in animals exposed perinatally to hormonally active agents during the critical period. |
ESTROGEN RECEPTOR EXPRESSION |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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ER
mRNA and ER protein in uterine epithelial cells were induced 4 and 12 h later, respectively, by a single injection of DES on day 0 (Sato et al., 1996a). ER in uterine epithelial cells was induced by neonatal injection of 17ß-estradiol or DES in a dose-dependent manner. The doses of DES and 17ß-estradiol which induce ER in neonatal mouse uterine epithelial cells are correlated with those which induce persistent changes in reproductive tracts in mice. ER was also detected in periosteum and bone cells of the pubis (Uesugi et al., 1992), and in anococcygeus muscle cells in mice (Fukazawa et al., 1997), which were also permanently affected by neonatal exposure to estrogen. In situ hybridization revealed that DES induced ER mRNA in uterine and vaginal epithelial cells 12 h after injection, and epithelial cell proliferation in ovariectomized adult mice (Sato et al., 1996a). Medlock et al. (1991) showed that ER mRNA level in the uterus of ovariectomized adult rats is reduced by 17ß-estradiol. In mice, DES acts as ER inducer in the uterus and vagina in both neonatal and ovariectomized adult mice (Sato et al., 1996a). Scrocchi and Jones (1991) reported that ER mRNA expression was not detected by Northern blot analysis in the vagina of mice exposed neonatally to 17ß-estradiol. However, we showed that the concentration of ER mRNA of the uterus of neonatally DES-exposed, ovariectomized adult mice was significantly higher than that of the DES-unexposed, ovariectomized controls (Kamiya et al., 1996). In the vagina of DES-exposed mice, however, ER mRNA was much lower in concentration than in the controls. These results coincide with the previous findings that ER was reduced by neonatal DES exposure (Bern et al., 1987), and that a small percentage of ER-immunoreactive cells were detected only in the basal layer in the vagina of DES-exposed mice (Sato et al., 1992). ER null mice which show no proliferative response to estrogen in female reproductive tracts have been extensively studied (see Couse and Korach, 1999). However, uterus and vagina retain responsiveness to estrogen in ERß null mice (Couse and Korach, 1999), suggesting that ovary-independent vaginal changes induced by perinatal estrogen exposure is mediated by ER. |
ONCOGENE, HOX GENE AND DNA DEMETHYLATIOM |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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The uterus and vagina of neonatally DES-exposed mice expressed high levels of c-jun and c-fos mRNAs (Kamiya et al., 1996
), which coincide with results showing a high mitotic activity in the uterus and vagina of mice treated neonatally with DES (Iguchi et al., 1985). In the vagina, however, the expression of c-jun and c-fos mRNAs in the DES-exposed mice was greater than in the control mice receiving 17ß-estradiol injection. The expression of c-jun and c-fos mRNAs in the uterus and vagina of the DES-exposed mice was not changed by the later 17ß-estradiol injection, supporting the previous results that sensitivity to 17ß-estradiol is low in neonatally estrogenized mouse reproductive tracts (Iguchi, 1992). Neonatal estrogen treatment increased the levels of uterine EGF and c-fos protein in adult mice (Falck and Forsberg, 1996). These findings suggest that neonatal exposure of estrogen to mice causes deregulated expression of c-jun and c-fos mRNAs in the postnatal vagina, resulting in estrogen-independent persistent proliferation and cornification and hyperplastic downgrowths of the vaginal epithelium.
Mice deficient for the Abdominal B (AbdB) Hox gene Hoxa-10 exhibit reduced fertility due to defects in implantation. During the peri-implantaion period Hoxa-10 is sequentially expressed in the uterine epithelium and stroma. Hoxa-10 expression in the adult uterus is activated by progesterone, and blocked by progesterone receptor antagonist RU486, and repressed by estrogen. Hoxa-9 and Hoxa-11 were also activated by progesterone but differentially regulated by estrogen. Hoxa-10 knockout mice showed uterine, cervical and oviductal malformations resembling those in perinatally DES-exposed mice and prenatally DES-exposed humans. Exposure of the developing female reproductive tract to DES, either in vivo or in organ culture, repressed the expression of Hoxa-10 in the Müllerian duct. The DES phenotype could be the result of transient, incomplete repression of multiple AbdB Hox genes, which are regulated by endogenous steroids (Ma et al., 1998). Mice lacking Wnt7a have malformed female reproductive tracts which closely resemble the reproductive tract morphogenesis observed in female mice prenatally exposed to DES (Miller and Sassoon, 1998). Fetal exposure to DES results in de-regulation of Wnt7a during uterine morphogenesis (Miller et al.,1998).
DNA methylation is known to regulate cellular physiology by altering gene expression and is programmed in the growth and differentiation processes. DNA demethylation of CpG/-464 immediately upstream from the estrogen response element in lactoferrin promoter was found in the uteri of mice treated neonatally with DES. This abnormal demethylation occurred in specific response to DES treatment in neonatal mice, but not in 30-day-old mice. This site remained methylated in the neonatally DES-treated/ovariectomized mice, indicating that this DES-elicited demthylation is under hormonal control. Thus, neonatal DES treatment appeared to imprint an abnormal, site-specific demethylation of CpG/-464, which normally requires ovarian hormones to occur in adult mice. The demethylation was maintained in uterine tumors of the neonatally DES-treated mice (Li et al., 1997).
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GROWTH FACTOR AND DEATH FACTOR EXPRESSION |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Neonatal estrogen exposure induced the permanent induction of EGF and lactoferrin (Teng et al., 1989
) that are normally under steroid hormone control. Expression of EGF and lactoferrin have been demonstrated to be persistent and are observed even in the adult animals exposed neonatally to DES (Nelson et al., 1994). We have also demonstrated that ovary-independent persistent expression of EGF and transforming growth factor- (TGF-) mRNAs in neonatally DES-exposed mouse vagina but not in uterus (Sato et al., 1996b). Several other genes, such as insulin-like growth factor (IGF)-I, IGF-II and keratinocyte growth factor (KGF) that are upregulated in the neonatally DES-exposed uterus decreased after ovariectomy, indicating that regulation of gene expression is altered by neonatal DES exposure. Persistent reduction of EGF receptor occurs in neonatally DES-exposed mouse vagina (Iguchi et al., 1993). Tumor necrosis factor- (TNF-) and Fas ligand may be associated with apoptotic cell death in mouse reproductive tracts (Suzuki et al., 1996). However, down regulation of these genes was found in neonatally DES-exposed uterus and vagina. Therefore, ovary-independent persistent proliferation of reproductive organs in neonatally DES-exposed mice can be partly explained by the down regulation of these death factors. The upregulated expression of estrogen-inducible genes, EGF and/or TGF-, as well as the downregulated expression of death factors, TNF- and/or Fas ligand, may play roles in the development of lesions and in the etiology of preneoplastic and neoplastic lesions that are manifested by estrogen treatment during development (Fig. 1).
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POLYOVULAR FOLLICLES |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Neonatal exposure of DES or 17ß-estradiol for 5 days from the day of birth causes an increased occurrence of polyovular follicles with 2–23 oocytes per follicle in ovaries of immature mice and polynuclear oocytes (Iguchi et al., 1986
). In DES-treated mice, polyovular follicle incidence was 120–340 times higher than in the controls. polyovular follicle incidence increased only when neonatal DES treatment was begun between days 0 and 3. Simultaneous injections of an aromatase inhibitor lowered the induction of polyovular follicles by testosterone, indicating that testosterone enhanced polyovular follicle formation is a result of its conversion to estrogen (Iguchi et al., 1988). The minimum daily dose of DES during neonatal life necessary to induce polyovular follicles was 10–3 µg per newborn mice for 5 days from the day of birth (Iguchi, 1985). Polyovular follicles also occurred in the ovaries of offspring of mice given injections of DES from days 15 to 18 of gestation. Polyovular follicle incidence in prenatally DES-exposed offspring was increased 33–112 times over controls (Iguchi and Takasugi, 1986). A high incidence of polyovular follicle was also found in newborn mouse ovaries transplanted for 30 days into ovariectomized hosts given DES injections. When neonatal ovaries were cultured in a serum-free medium for 5 days containing DES and then transplanted into ovariectomized hosts, polyovular follicles were found in the grafts (Iguchi et al., 1990). Polyovular follicles also occur in humans and may be stimulated by an activated gonadotropin-estrogen axis (Dandekar et al., 1988). Guillette et al. (1994) reported that female alligators from Lake Apopka, contaminated with extensive spill of xenoestrogens, dicofol and DDT or its metabolites, exhibited abnormal ovarian morphology with large numbers of polyovular follicles and polynuclear oocytes, showing a close connection between wild-life and laboratory rodents exposed to estrogenic compounds in early life. The presence of polyovular follicles can be used as a marker of early exposure to xenoestrogens in alligators as well as mice. |
REDUCTION OF FERTILIZABILITY |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Polyovular follicle induced by neonatal DES exposure were ovulated by injections of gonadotropins (Iguchi et al., 1990
). Seventy-seven % of oocytes from uniovular follicles of control mice developed up to 8-cell stage embryos following in vitro insemination; 66% of those from similar follicles of DES-exposed mice developed to the same stage. By contrast, only 47% of oocytes from polyovular follicles of DES-exposed mice showed division up to the 8-cell stage, indicating a significantly lower fertilization rate compared to the oocytes from uniovular follicles of control and DES-exposed mice. Menczer et al. (1986) demonstrated that women exposed to DES in utero showed higher rates of infertility and anatomical structural defects. After treatment with ovulation-stimulating drugs, spontaneous abortion and tubal pregnancy were frequent in DES-exposed women. Halling and Forsberg (1990) showed that grafting of control ovaries to DES-exposed females never resulted in pregnancy. DES-exposed females were treated with gonadotropins and artificially inseminated. Most zygotes died in the oviduct of DES-exposed females. When the early embryos were cultured in vitro, several survived to the implantation stage but survival was lower than controls, suggesting that both an egg factor and an oviductal factor were responsible for early embryonic death in DES-exposed females (Halling and Forsberg, 1991).
Walker and Kurth (1995) reported that DES has a multi-generational effect transmitted through the blastocyst, which is consistent with fetal germ cell mutation from DES-exposed mice. In DES-exposed daughters and sons, no evidence for transgenerational effects were reported (Giusti et al., 1995; Mittendorf, 1995). Halling and Forsberg (1992) and Halling et al. (1993) suggested that the oviductal factor(s) harmful to the embryo is related to a persistent and increased level of circulating estrogen in neonatally DES-exposed females. However, it is also possible that hormones and growth factors needed for early embryonic development were deficient in the oviducts of DES-exposed mothers.
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ABNORMALITIES IN SKELETAL TISSUE AND MUSCLE |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Nongenital abnormalities, such as immune system, central nervous system, hypothalamohypophysial complex and behavior have also been reported in mice exposed perinatally to sex hormones and antihormones (see Takasugi and Bern, 1988
; Iguchi and Ohta, 1996). A breakdown of symphysial bone and cartilage replacement by connective tissue occurs. Estrogen feminizes the bone structure of the pelvis and pubic symphysis in many mammals (Iguchi et al., 1995). The shape of the innominate bone is transformed to the male type under the influence of early postnatal androgen. Neonatal treatment with tamoxifen induces elongation of the pubic ligament, and retards the growth of the ilium and pubis in mice by changing the activities of osteoclasts and osteoblasts. Tamoxifen acts directly on the neonatal mouse pubis and os penis to inhibit its ossification (Iguchi et al., 1990; Iguchi, 1992; Iguchi and Ohta, 1996). Neonatal DES exposure induced persistent reduction of calcium and phosphorus in the pelvis and femur in aged mice (Fukazawa et al., 1996), indicating that neonatal DES and tamoxifen exposure result in permanent changes in bone tissue in mice.
The anococcygeus muscle is a paired smooth muscle in the perineal area, which shows sexual dimorphism; the muscle in male mice is significantly larger than in females (Fukazawa et al., 1997). Neonatal exposure to DES significantly reduced the muscle in male mice, but strikingly increased the female muscles. The muscle of neonatally DES-exposed female mice was significantly larger than the controls, and ovariectomy did not alter this, indicating that DES had an irreversible stimulatory effect on the muscle of neonatal female mice. These examples suggest that more attention should be paid to abnormalities in nongenital organs exposed to various estrogenic agents during embryonic, fetal and early postnatal development in mammals including humans.
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BISPHENOL A |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Bisphenol A is a monomer of polycarbonate plastics and a constituent of epoxy and polystyrene resins that are extensively used in the food-packaging industry and in dentistry. Bisphenol A has been shown to mimic estrogen both in vivo and in vitro (Krishnan et al., 1993
), stimulates prolactin secretion and the expression of a prolactin regulating factor from the posterior pituitary in the estrogen-sensitive Fisher 344 rat, but not in Sprague-Dawley rats (Steinmetz et al., 1997). Four daily injections of bisphenol A stimulated uterine and vaginal weight and cell proliferation in the uterus and vagina of ovariectomized ICR mice (Fig. 3), and a single high doses of bisphenol A (37.5–150 mg/kg) induced cell proliferation in the uterus and vagina, and increased c-fos mRNA in ovariectomized F344 rats (Steinmetz et al., 1998). Treatment of Fisher 344 rats for 3 days with continuous release capsules that supplied a much lower dose of bisphenol A (0.3 mg/kg/day) resulted in hypertrophy, hyperplasia, and mucus secretion in the uterus and hyperplasia and cornification of the vaginal epithelium. The same concentration of bisphenol A can be found in the serum and liver of both the 17-day-old fetus and mother 30 min after a single injection to the pregnant mother. Thirty min after injection, bisphenol A was found in brain, uterus and testis in the fetus (Uchida, Sato and Iguchi, unpublished data). We also found bisphenol A in the human umbilical cord (0.85–3.11 ng/g wet tissue) (Takada et al., 1998). UDP-glucuronosyltransferase acts as detoxification of bisphenol A (Yokota et al., 1999). Gene expression of the enzyme was found in the liver of adult male and female rats, but not that of fetus and neonates. The enzyme activity appeared in 3-day-old rats (25–27% of adults), gradually increased at 7 days of age (30%) and reached a plateau at 2–2.5 weeks of age (Yokota et al., 1998), suggesting that pregnant mothers should avoid consuming bisphenol A.
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THE THREAT OF ENVIRONMENTAL ESTROGENS |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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Recently much evidence has accumulated showing that environmental estrogenic agents (pesticides, herbicides, polychlorinated compounds, plasticizers and alkylphenols) may affect human and animal populations including wildlife. The action of such agents during embryonic and fetal development demands extensive attention (Colborn et al., 1993
). The issue involved is not only the possible occurrence of birth defects but also the possible longterm effects which in humans may not manifest themselves until adolescence and even much later in life. As these effects may result in structural, reproductive, endocrinological, metabolic, immunological, neurological, behavioral, dysplastic, and neoplastic changes, the search for the consequences on the offspring of exposure during intrauterine life must be stringent and diversified (see Takasugi and Bern, 1988; Iguchi and Bern, 1996). Analyses of transgenerational effects of xenobiotic agents are needed in order to allow potential dangers to human and wildlife population to be estimated and confronted.
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ACKNOWLEDGMENTS |
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The authors thank Dr. Raphael Guzman of the Cancer Research Laboratory and Department of Molecular and Cell Biology at the University of California at Berkeley for his critical reading of this manuscript. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan, a research grant from Kihara Science Foundation, and a grant in Support of the Promotion of Research at Yokohama City University.
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FOOTNOTES |
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1 From the symposium of Endocrine Disrupting Contaminants: From Gene to Ecosystems presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 6–10 January 1999, at Denver, Colorado.
2 E-mail: taisen{at}nibb.ac.jp
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REFERENCES |
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SYNOPSISINTRODUCTIONHYPOTHALAMO-HYPOPHYSIAL AXISESTROGEN RECEPTOR EXPRESSIONONCOGENE, HOX GENE AND...GROWTH FACTOR AND DEATH...POLYOVULAR FOLLICLESREDUCTION OF FERTILIZABILITYABNORMALITIES IN SKELETAL TISSUE...BISPHENOL ATHE THREAT OF ENVIRONMENTAL...REFERENCES |
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