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Biomedical subjects

J A McLachlan

Publications and source records attributed to J A McLachlan.

At least 19 recordsLinked to original sources
PubMed1999

Interaction of PAHs and PCBs with ecdysone-dependent gene expression and cell proliferation.

This study was done to determine whether PAHs and PCBs can interact with the arthropod steroid hormone system. Ecdysteroid molting hormones control growth, molting, and reproduction in arthropods. A spike in 20-OH ecdysone (20 HE) triggers the molt cycle in crustaceans, and earlier studies have shown that PAHs can affect this molt cycle in several crab species. However, the mechanism of this molt cycle interaction is unknown. Both PAHs and PCBs interact with other nuclear receptors; however, nothing is known about their ability to interact with the invertebrate ecdysone receptor (EcR). Four PAHs, benzo[a]pyrene, benzo[b]fluoranthene, pyrene, and chrysene, and the commercial PCB mixture, Aroclor 1254, were used to determine the ability of these classes of compounds to induce ecdysone-dependent reporter gene expression and to modify the proliferation and differentiation response of the ecdysteroid-responsive Cl.8+ cell line. The four PAHs were each able to enhance the ecdysteroid response in both the reporter gene and the cell proliferation assays only when given in conjunction with ecdysteroids. Aroclor 1254 had no effect in either system, either alone or in conjunction with ecdysteroids. These studies show that although the PAHs alone do not activate ecdysteroid-dependent gene expression or cell differentiation, they are able to enhance the effect of ecdysteroids, presumably through a non-receptor-mediated process. This mechanism may explain the effects on molting which have been reported after low-level crude oil exposures in crustaceans.

Animals↗
PubMed1999

Alteration of leopard frog (Rana pipiens) metamorphosis by the herbicide acetochlor.

Based on the geographic correlation between the use of the pre-emergent herbicide acetochlor [2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl) acetamide] and the natural range of Northern leopard frogs (Rana pipiens), we investigated the effects of acetochlor (ACETO) on frog metamorphosis. We specifically examined the interaction of ACETO with thyroid hormone (T3) and corticosterone (CORT), hormones that regulate natural metamorphosis. ACETO, T3, and CORT were administered via immersion. Growth, developmental stage, and onset of metamorphic climax (forelimb emergence, FLE) were measured. We examined three hypotheses: (1) ACETO may alter metamorphosis. Premetamorphic tadpoles with low endogenous T3 were exposed to ACETO +/- 10(-9) M T3 for 7 days. 67% of tadpoles exposed to ACETO + T3 attained FLE, while 0% of T3 treated animals did. (2) ACETO mimics T3 action at the thyroid receptor (TR). Tadpoles were pretreated with T3 for 3 days to induce TR expression, then treated for 7 days with vehicle (DMSO), T3, or ACETO +/- T3. ACETO treatment after T3 priming did not accelerate FLE, suggesting that ACETO does not interact directly with the TR. Cotreatment with ACETO + T3 after T3 priming accelerated FLE relative to tadpoles primed with T3, then treated with T3. Because the ACETO + T3 acceleration of FLE appeared similar to the effect of CORT, we examined a third hypothesis: (3) ACETO may interact with CORT to accelerate FLE. Premetamorphic tadpoles were exposed to various doses of ACETO +/- T3 in the presence or absence of 10(-7) M CORT. CORT inhibited growth and hindlimb development and delayed FLE. ACETO never inhibited growth or hindlimb development, but ACETO did counteract the effects of CORT when T3 was present. ACETO consistently accelerated T3-induced metamorphosis, apparently interacting with T3 via a non-TR-mediated mechanism.

Animals↗
PubMed1999

Fathead minnow (Pimephales promelas) vitellogenin: purification, characterization and quantitative immunoassay for the detection of estrogenic compounds.

The egg yolk precursor protein, vitellogenin (VTG), was purified from blood plasma of 17beta-estradiol (E2)-treated male fathead minnows (Pimephales promnelas) by anion-exchange chromatography on DEAE-agarose. A rabbit antiserum was raised against their blood plasma and then adsorbed with plasma from untreated (control) males to render the antiserum specific to VTG. The adsorbed antiserum was used to detect fathead minnow VTG (fVTG) in Western and dot blotting experiments and in an enzyme-linked immunosorbent assay (ELISA). The antiserum recognised fVTG as a approximately 156 kDa protein in plasma from vitellogenic females and E2-injected males but not untreated males. Its identity was confirmed by analysis of: (1) amino acid composition; (2) an internal amino acid sequence; (3) reactivity to the homologous antiserum; and (4) recognition by monoclonal antibodies prepared against the VTG from common carp (Cyprinus carpio) and brown bullhead (Ameiurus nebulosus). Specificity of the homologous antiserum to fVTG was confirmed by Western blotting of serially diluted plasma from vitellogenic females. Utility of the antiserum and purified fVTG for detecting exposure of male fathead minnows to estrogenic compounds was verified using a dot blotting immunoassay of fVTG and detected by chemiluminescence. Adult male fish were exposed to various concentrations of E2 (10(-8), 10(-9) and 10(-10) M) in their rearing water and plasma assayed for the presence of VTG at different time points (2, 7, 14 and 21 days). A competitive, antibody-capture, quantitative ELISA was then developed based on the purified fVTG and its respective antiserum. The ELISA was validated by demonstrating parallel binding slopes of dilution curves prepared with plasma from E2-injected males, vitellogenic females, and aqueous egg extracts as compared with purified fVTG standard. Plasma concentrations of VTG as low as 3 ng ml(-1) were detected in the ELISA, for which inter- and intra-assay coefficients of variation were both less than 5%. Furthermore, plasma from control males was unreactive with the fVTG antiserum. The VTG ELISA could be useful for the detection of estrogenic properties associated with certain compounds and could be easily incorporated into standard laboratory toxicity assays using this species.

Amino Acid Sequence↗
PubMed1999

Effects of environmental estrogens on tumor necrosis factor alpha-mediated apoptosis in MCF-7 cells.

Environmental estrogens represent a class of compounds which have been shown to mimic the effects or activity of the naturally occurring ovarian hormone 17beta-estradiol. Given the role of 17beta-estradiol in cell survival in a number of systems, we wished to determine if environmental estrogens protect MCF-7 cells from apoptosis. Here we demonstrate that the organochlorine pesticides o, p' DDT and alachlor, like 17beta-estradiol, have the ability to suppress tumor necrosis factor alpha (TNF)-induced apoptosis in estrogen receptor (ER)-positive MCF-7 breast carcinoma cells. These compounds, however, did not affect TNF-induced apoptosis of the ER-negative MDA-MB-231 cell line. The ability of these compounds to suppress apoptosis in MCF-7 cells was correlated with an ER-dependent increase in Bcl-2 expression. Taken together these results demonstrate that estrogenic organochlorine pesticides like o, p' DDT and alachlor may partially mimic the primary endogenous estrogen, 17beta-estradiol, and function to suppress apoptosis in ER-responsive cells.

Apoptosis↗
PubMed1999

Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin.

Organochlorine compounds, particularly polychlorinated biphenyls (PCBs), alter serum thyroid hormone levels in humans. Hydroxylated organochlorines have relatively high affinities for the serum transport protein transthyretin, but the ability of these compounds to interact with the human thyroid receptor is unknown. Using a baculovirus expression system in insect cells (Sf9 cells), we produced recombinant human thyroid receptor ss (hTRss). In competitive binding experiments, the recombinant receptor had the expected relative affinity for thyroid hormones and their analogs. In competitive inhibition experiments with PCBs, hydroxylated PCBs (OH-PCBs), DDT and its metabolites, and several organochlorine herbicides, only the OH-PCBs competed for binding. The affinity of hTRss for OH-PCBs was 10,000-fold lower (Ki = 20-50 microM) than its affinity for thyroid hormone (3,3',5-triiodothyronine, T3; Ki = 10 nM). Because their relative affinity for the receptor was low, we tested the ability of OH-PCBs to interact with the serum transport proteins--transthyretin and thyroid-binding globulin (TBG). With the exception of one compound, the OH-PCBs had the same affinity (Ki = 10-80 nM) for transthyretin as thyroid hormone (thyroxine; T4). Only two of the OH-PCBs bound TBG (Ki = 3-7 microM), but with a 100-fold lower affinity than T4. Hydroxylated PCBs have relatively low affinities for the human thyroid receptor in vitro, but they have a thyroid hormonelike affinity for the serum transport protein transthyretin. Based on these results, OH-PCBs in vivo are more likely to compete for binding to serum transport proteins than for binding to the thyroid receptor.

Binding, Competitive↗
PubMed1998

Estrogen-dependent gene regulation by an oxidative metabolite of diethylstilbestrol, diethylstilbestrol-4',4"-quinone.

Diethylstilbestrol (DES) is a well-characterized carcinogen in humans and animals although its mechanisms of carcinogenicity are not yet known. While the estrogenic activity of DES is important, there is evidence that oxidative metabolism also plays an important role for its toxicity. DES is oxidatively metabolized in vivo and in vitro to a number of compounds including diethylstilbestrol-4',4"-quinone (DQ), an unstable and reactive intermediate, and Z,Z-dienestrol (ZZ-DIEN). Estrogen receptor (ER) binding assays with mouse uterine cytosol indicate that DES, DQ and ZZ-DIEN have relative binding affinities of 286, 3.6 and 0.3, respectively, relative to estradiol as 100. In addition, DQ binds irreversibly and specifically to ER suggesting that DQ may be biologically active despite its rapid metabolism and lower binding affinity compared to DES. To test this, COS-1 cells were transfected with an estrogen responsive reporter construct containing of VitA2 estrogen response element (ERE) with or without an ER expression vector. In the presence of ER, treatments with DES, DQ and ZZ-DIEN resulted in 11, 10, and 2-fold induction of chloramphenicol acetyltransferase (CAT) activity, respectively. This induction was mediated by estrogen receptor since it was suppressed by pretreatment with a 10-fold excess of the pure antiestrogen ICI 182,780. These data indicate that DQ is a biologically active intermediate that is capable of transactivation of estrogen responsive genes through the ER. Furthermore, the data suggest that the ability of DQ to irreversibly bind ER may result in persistent stimulation of ER. This persistent stimulation may be related to the carcinogenicity of DES.

Animals↗
PubMed1998

Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol.

Prenatal exposure to diethylstilbestrol (DES) has been associated with the subsequent development of reproductive tract abnormalities, including poor reproductive outcome and neoplasia, in experimental animals and humans. Experimental animal studies with chemical carcinogens have raised the possibility that adverse effects of DES may be transmitted to succeeding generations. To evaluate this possibility and to determine if there is a sensitive window of developmental exposure, outbred CD-1 mice were treated with DES during three stages of development: group 1 was treated on days 9-16 of gestation (2.5, 5 or 10 microg/kg maternal body wt), the time of major organogenesis; group II was treated once on day 18 of gestation (1000 microg/kg maternal body wt) just prior to birth; group III was treated on days 1-5 of neonatal life (0.002 microg/pup/day). Female mice (F1) in each group were raised to sexual maturity and bred to control males. As previously reported, fertility of the F1 DES-exposed females was decreased in all groups. Female offspring (DES lineage or F2) from these matings were raised to maturity and housed with control males for 20 weeks. The fertility of these DES lineage female mice was not affected by DES exposure of their 'grandmothers'. DES lineage mice were killed at 17-19 and 22-24 months of age. An increased incidence of malignant reproductive tract tumors, including uterine adenocarcinoma, was seen in DES lineage mice but not in corresponding controls; the range and prevalence of tumors increased with age. Because uterine adenocarcinomas were seen in all three DES groups, all developmental exposure periods were considered susceptible to the adverse effects of DES. These data suggest that the reduced fertility observed in the DES F1 female mice was not transmitted to their descendants; however, increased susceptibility to tumor formation is apparently transmitted to subsequent generations.

Animals↗
PubMed1998

Are estrogens carcinogenic during development of the testes?

Many chemicals in the environment mimic the female sex hormone, estrogen. Exposure to environmental estrogens during early fetal development was proposed by Sharpe & Skakkebaek as a potential risk factor for subsequent testicular disease, including neoplasia and poor semen quality. To understand the mechanisms of action of estrogenic chemicals during differentiation of the male genital tract, we have studied developmental exposure to the synthetic estrogen, diethylstilboestrol (DES). While DES is a much more potent estrogen than most environmental chemicals examined, several of these compounds share some of the same properties as DES, such as a relative lack of binding to serum estrogen carrying proteins. Prenatal exposure to DES is associated with poor semen quality, prostatic disease, cryptorchidism and testicular neoplasia in mice. A rare form of testicular cancer, rete testis carcinoma, was observed in five percent of male mice treated in utero with DES. We also demonstrated altered regulation of an estrogen responsive gene, lactotransferrin (LTF) in the seminal vesicles of treated mice, but not the controls. Likewise, LTF was irreversibly altered in the uteri of developmentally treated females; at the molecular level altered methylation of the gene appears to be involved, thus, providing a potential marker for hormonal effects during development. The induction of permanent or "imprinted" responses during the development of a relatively estrogen-free reproductive tract cell suggests that undifferentiated targets for estrogen action may be sites for subsequent growth and differentiation defects associated with neoplasia.

Animals↗
PubMed1998

Environmental signaling: a biological context for endocrine disruption.

Endogenous and exogenous chemical signals have evolved as a means for organisms to respond to physical or biological stimuli in the environment. Sensitivity to these signals can make organisms vulnerable to inadvertent signals from xenobiotics. In this review we discuss how various chemicals can interact with steroid-like signaling pathways, especially estrogen. Numerous compounds have estrogenic activity, including steroids, phytoestrogens, and synthetic chemicals. We compare bioavailability, metabolism, interaction with receptors, and interaction with cell-signaling pathways among these three structurally diverse groups in order to understand how these chemicals influence physiological responses. Based on their mechanisms of action, chemical steroid mimics could plausibly be associated with recent adverse health trends in humans and animals.

Animals↗
PubMed1998

Children's health and the environment: a new agenda for prevention research.

Patterns of illness in American children have changed dramatically in this century. The ancient infectious diseases have largely been controlled. The major diseases confronting children now are chronic and disabling conditions termed the "new pediatric morbidity"--asthma mortality has doubled; leukemia and brain cancer have increased in incidence; neurodevelopmental dysfunction is widespread; hypospadias incidence has doubled. Chemical toxicants in the environment as well as poverty, racism, and inequitable access to medical care are factors known and suspected to contribute to causation of these pediatric diseases. Children are at risk of exposure to over 15,000 high-production-volume synthetic chemicals, nearly all of them developed in the past 50 years. These chemicals are used widely in consumer products and are dispersed in the environment. More than half are untested for toxicity. Children appear uniquely vulnerable to chemical toxicants because of their disproportionately heavy exposures and their inherent biological susceptibility. To prevent disease of environmental origin in America's children, the Children's Environmental Health Network (CEHN) calls for a comprehensive, national, child-centered agenda. This agenda must recognize children's vulnerabilities to environmental toxicants. It must encompass a) a new prevention-oriented research focus; b) a new child-centered paradigm for health risk assessment and policy formulation; and c) a campaign to educate the public, health professionals, and policy makers that environmental disease is caused by preventable exposures and is therefore avoidable. To anchor the agenda, CEHN calls for long-term, stable investment and for creation of a national network of pediatric environmental health research and prevention centers.

Child↗
PubMed1997

Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus.

Alteration of DNA demethylation in five CpG sites (-547, -533, -475, -464, and -454) immediately upstream from the estrogen response element of lactoferrin promoter was determined in the uteri of immature (17-day-old) and mature (21- and 30-day-old) mice treated neonatally with DES. Only the CpG/-464 was found to be abnormally demethylated by diethylstilbestrol (DES) treatment in the mature uteri. This abnormal demethylation occurred in specific response to DES in neonatal mice, because DES injected into the 30-day-old mature mice did not demethylate CpG/-464. This site, however, remained methylated in the neonatally DES-treated/ovariectomized mice, indicating that this DES-elicited demethylation is under hormonal control. Thus, neonatal DES treatment appeared to imprint an abnormal, site-specific demethylation of CpG/-464, which requires ovarian hormones to occur in adult mice. Moreover, the demethylation was maintained in uterine tumors of the neonatally DES-treated mice. This mode of demethylation is reminiscent of uterine tumor formation, which also depends on both neonatal DES exposure and ovarian hormone stimulation in adulthood. Thus, neonatal DES treatment may induce tumor formation as well as demethylation through a common cellular process.

Age Factors↗
PubMed1997

Evaluation of clinical and environmental anti-estrogens with human estrogen receptor expressed in Saccharomyces cerevisiae: a novel role for ABC-cassette transporters in mediating anti-estrogenic activity.

The effectiveness of anti-estrogens in treating estrogen-dependent diseases is limited by the acquired resistance of some diseases to anti-estrogens. This effect could occur by the export of anti-estrogens by cell membrane transport proteins. To study this phenomenon we have expressed human estrogen receptor (hER) and an estrogen-sensitive reporter in wild-type yeast and two transport-defective strains. In the wild-type strain, the most effective anti-estrogen was nafoxidine. 4-Hydroxy tamoxifen and clomiphene were inactive whereas tamoxifen had significant inhibitory activity in the wild-type strain. Using a strain missing the ABC-cassette transporter Snq2, clomiphene had anti-estrogenic activity. 4-Hydroxy tamoxifen had anti-estrogenic activity only in yeast lacking the transporter Pdr5. Whole cell binding assays indicated that 4-hydroxy tamoxifen is exported by Pdr5. Environmental chemicals such as polychlorinated biphenyls function as partial estrogens and anti-estrogens in yeast. In the absence of Pdr5 or Snq2, the estrogenic activity of 4-hydroxy, 2',4',6'-trichloro biphenyl (3-PCB) was substantially reduced in comparison to its activity in the wild-type strain. Interestingly, the antiestrogenic activity of 3-PCB was equivalent in the wild-type and transporter-defective strains. Our results suggest a novel role for ABC-cassette transporters in regulating the activity of clinical and environmental anti-estrogens.

ATP-Binding Cassette Transporters↗
PubMed1997

Synergistic responses of steroidal estrogens in vitro (yeast) and in vivo (turtles).

Many environmental agents exert estrogenic activity. Previous studies from our laboratories demonstrated that certain combinations of environmental estrogens (i) reverse the sex of male turtle embryos in a synergistic manner (Bergeron et al., (1994) Environ. Hlth Perspect. 102, 780-782), and (ii) synergistically transactivate the human estrogen receptor (hER) in yeast and mammalian cells (Arnold et al., (1996) Science 272, 1489-1492). Because our findings with synthetic estrogens suggested that combinations of naturally-occurring steroidal estrogens might also produce synergistic activity of the ER, we used the same model systems to measure the activity of combinations of steroidal estrogens. The activity of combinations of estrone, estradiol-17beta or estradiol-17alpha in yeast strains expressing hER was synergistic at submaximal concentrations of both estrogenic compounds. However, synergy was not observed with mixtures of estrogens when the concentration of one of the estrogens alone was maximally active in yeast. Ligand-binding assays in yeast performed with various radiolabeled estrogens suggested that multiple estrogens may interact with the receptor. The estrogen-dependent process of sex-reversal of turtle embryos incubated at a male-producing temperature was used to determine whether steroidal estrogens also had synergistic activity in vivo. In this instance, a combination of estriol and estradiol-17beta was effective in reversing the gonadal sex of turtle embryos from males to females in a synergistic manner. Our results suggest that the synergy of some combinations of estrogens, synthetic or steroidal, may play a role in the estrogen-dependent process of sexual development in certain species.

Animals↗
PubMed1997

o,p'-DDT and its metabolites inhibit progesterone-dependent responses in yeast and human cells.

Using a combination of in vitro assays we have evaluated whether DDT metabolites can interact with the progesterone receptor pathway in yeast expressing human progesterone receptor (hPR) and in T47D human breast cancer cells which express endogenous hPR. In transactivation assays using both yeast and T47D cells, o,p'-DDT and the metabolites p,p'-DDT, o,p'-DDD, p,p'-DDD, o,p'-DDE, p,p'-DDE, p,p'-DDA, and DDOH inhibited progesterone-induced reporter gene activity in a dose-dependent manner. None of the DDT metabolites functioned as hPR agonists. Whole cell competition binding assays using T47D cells indicated that the inhibitory effects of DDT metabolites on progesterone-dependent activites may occur through both hPR-dependent and hPR-independent pathways. Our results and previous reports of DDT metabolites interacting with estrogen and androgen receptors suggests that this class of environmental chemicals may interact with numerous hormone receptor signaling pathways.

Binding, Competitive↗
PubMed1997

Several synthetic chemicals inhibit progesterone receptor-mediated transactivation in yeast.

The human progesterone receptor (hPR) B-form and a progesterone-sensitive reporter were expressed in yeast and used to screen a library of synthetic chemicals for their ability to function as agonists or antagonists of hPR. The transcriptional activity of hPR was not increased in the presence of over 40 individual chemicals. Seven chemicals decreased progesterone-dependent activity in yeast. The most effective chemicals were 6-hydroxychrysene, 1-hydroxypyrene, 4-hydroxy, 2',4',6'-trichloro biphenyl, and 4-hydroxy, 2',3',4',5'-tetrachloro biphenyl. The decrease of progesterone-mediated transactivation strongly correlated with their displacement of [3H]progesterone from hPR. The absence of the hydroxyl group on the above chemicals completely abolished their inhibitory activity. The other chemicals which decreased progesterone activity were endosulfan II, endosulfan sulfate, and lindane. These chemicals did not inhibit [3H]progesterone binding, suggesting that they inhibit progesterone action by interacting with a region of hPR distinct from binding [3H]progesterone or by a mechanism independent of hPR. These results highlight the utility of yeast for screening hormonally-active chemicals. In addition, hydroxylation appears to be essential for the interaction of some chemicals with hPR.

Humans↗
PubMed1997

Identification and characterization of estrogen and progesterone receptors from the oviduct of the American alligator (Alligator mississippiensis).

A protein extract prepared from the egg shell fiber-secreting region of the oviduct of Alligator mississippiensis was assayed for the presence of receptors for estrogen and progesterone. In the presence of [3H]-estradiol-17 beta, the extract contained an estrogen-binding activity which reached equilibrium at 25 degrees C in 1 h. Scatchard analysis demonstrated that a single estrogen-binding activity was present in the extract with a Kd of 0.5 nM for [3H]estradiol-17 beta. A steroid specificity competition assay showed the estrogen binding activity strongly recognized estradiol-17 beta and diethylstilbestrol (DES) and weakly interacted with estrone, estriol, estradiol-17 alpha, and dihydrotestosterone (DHT). The estrogen binding activity did not recognize testosterone, dexamethasone or progesterone. The extract exhibited a DNA-binding activity that recognized an estrogen response element in a gel mobility shift assay. We have also identified a high affinity binding activity in the extract that specifically recognized the synthetic progestin R5020 with a Kd of 0.9 nM. This binding activity recognized 17 alpha-estradiol, dexamethasone, testosterone, and estriol. This activity did not recognize DHT, DES, or estradiol-17 beta. These data suggest the presence of estrogen and progesterone receptors in the oviduct of the alligator.

Alligators and Crocodiles↗
PubMed1997

Accelerated onset of uterine tumors in transgenic mice with aberrant expression of the estrogen receptor after neonatal exposure to diethylstilbestrol.

The role of estrogen and the estrogen receptor (ER) in the induction and promotion of tumors was investigated by using transgenic MT-mER mice, which overexpress the ER. It was hypothesized that because of this abnormal expression of the ER, the reproductive-tract tissues of the MT-mER mice may be more susceptible to tumors after neonatal exposure to the potent synthetic estrogen diethylstilbestrol (DES). Normally non-estrogen responsive tissues that may have expressed ER as a result of the transgene were also studied for DES-induced tumors. Wild-type and MT-mER littermates were treated with 2 micrograms/pup/d DES 1-5 d after birth and then killed at 4, 8, 12, and 18 mo of age. The DES-treated MT-mER mice demonstrated a significantly higher incidence of uterine adenocarcinoma at 8 mo (73%) than the DES-treated wild-type mice (46%). The tumors of the MT-mER mice were often more aggressive than those in the wild-type animals. These tumors were also preceeded at 4 mo by a significantly higher incidence of the preneoplastic lesion atypical hyperplasia in the MT-mER mice (26% compared with 0% in the wild-type mice). Other DES-induced abnormalities were observed at equal rates in the wild-type and MT-mER mice. Although no tumors were observed in untreated wild-type females, a single untreated MT-mER female had uterine adenocarcinoma at 18 mo. These data indicate that the level of ER present in a tissue may also be a determining factor in development of estrogen-responsive tumors.

Adenocarcinoma↗