During development, 17alpha-estradiol is a potent estrogen and carcinogen.

Hajek, Richard A.; Robertson, Audra D.; Johnston, Dennis A.; Van, Nguyen T.; Tcholakian, Robert K.; Wagner, Laura A.; Conti, Claudio J.; Meistrich, Marvin L.; Contreras, Nancy; Edwards, Creighton L.; Jones, Lovell A.

doi:10.1289/ehp.97105s3577

Cited by 14 publications

(5 citation statements)

References 22 publications

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“…A limitation of this study was the number of doses used, but there appeared to be a pattern of increased CV-tract tumors with the higher doses. These data strongly support the theory that relatively weak estrogens can induce tumors in mice when exposure occurs during a critical period of development ( Hajek et al 1997 ).…”

Section: Discussionsupporting

confidence: 87%

“…The neonatal mouse model has been extensively studied for more than four decades and has proven extremely valuable in assessing human in utero exposure to DES. The defined period for causation of genital tract tumors by natural (17α-estradiol and E 2 ) and synthetic (e.g., DES) estrogens occurs during the development of the reproductive tract in both humans and rodents ( Hajek et al 1997 ). The use of the neonatal mouse model was necessary because, unlike findings in adult-treated rodents ( Liehr et al 1986 ), an apparent correlation between estrogenicity and carcinogenicity exists in neonatally treated rodents ( Newbold et al 1990 , 1997 ).…”

Section: Discussionmentioning

confidence: 99%

“…17α-Estradiol is a natural estrogen that binds weakly to the estrogen receptor (ER). In mice, exposure to 17α-estradiol during a critical period of reproductive tract development leads to subsequent gynecologic malignancies ( Hajek et al 1997 ). These studies exemplify that various abnormalities in long-term studies are dependent on when mammals are exposed to a natural or synthetic estrogen.…”

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confidence: 99%

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Long-Term Effects of Neonatal Exposure to Hydroxylated Polychlorinated Biphenyls in the BALB/cCrgl Mouse

Martinez

Stephens

Jones³

2005

Environ Health Perspect

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The neonatal mouse model has been a valuable tool in determining the long-term effects of early exposure to estrogenic agents in mammals. Using this model, we compared the effects of 2′,4′,6′-trichloro-4-biphenylol (OH-PCB-30) and 2′,3′,4′,5′-tetrachloro-4-biphenylol (OH-PCB-61) as prototype estrogenic hydroxylated PCBs (OH-PCBs) because they are reported to exhibit relatively high estrogenic activity both in vivo and in vitro. The purpose of this study was to examine the relationship between estrogenicity and carcinogenicity of OH-PCB congeners. The OH-PCBs were tested individually and in combination to determine whether effects of combined OH-PCBs differed from those of these OH-PCBs alone. We evaluated the long-term effects of neonatal exposure to OH-PCBs with treatment doses that were based on the reported binding affinity of specific OH-PCB congeners to estrogen receptor α. BALB/cCrgl female mice were treated within 16 hr after birth by subcutaneous injections every 24 hr, for 5 days. The mice treated with OH-PCB-30 (200 μg/day) or 17β-estradiol (5 μg/day) showed similar increased incidences of cervicovaginal (CV) tract carcinomas (43% and 47%, respectively). In addition, when mice were treated with OH-PCBs as a mixture, a change in the type of CV tract tumor was observed, shifting from predominantly squamous cell carcinomas to adenosquamous cell carcinoma. From our results, we conclude that the individual OH-PCBs tested were estrogenic and tumorigenic in mice when exposed during development of the reproductive tract. These data support the hypothesis that mixtures may act differently and unexpectedly than do individual compounds.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Long-Term Effects of Neonatal Exposure to Hydroxylated Polychlorinated Biphenyls in the BALB/cCrgl Mouse

Martinez

Stephens

Jones³

2005

Environ Health Perspect

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“…Thus, the purpose of this study was to determine the severity of ageassociated OA in genetically heterogeneous male mice and determine if the severity of ageassociated OA was reduced in mice treated with selected agents in the ITP study that were found to increase life span. Findings were compared to Ames dwarf mice, which are deficient in growth hormone and are genetically long-lived 16 .…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring osteoarthritis in male mice with an extended lifespan

Ewart

Harper²,

Gravely

et al. 2019

Connective Tissue Research

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Aim-The purpose of this study was to evaluate whether pharmacologic treatments or genotypes shown to prolong murine lifespan ameliorate the severity of age-associated osteoarthritis.Materials and Methods-Male UM-HET3 mice were fed diets containing 17-α-estradiol, acarbose, nordihydroguaiaretic acid, or control diet per the National Institute on Aging Interventions Testing Program (ITP) protocol. Findings were compared to genetically long-lived male Ames dwarf mice. Stifles were analyzed histologically with articular cartilage structure (ACS) and safranin O scoring as well as with quantitative histomorphometry.Results-Depending on the experimental group, ITP mice were between 450-1150 days old at the time of necropsy and 12-15 animals were studied per group. Two age groups (450 and 750 days) with 16-20 animals per group were used for Ames dwarf studies. No differences were found in the ACS or safranin O scores between treatment and control groups in the ITP study. There was high variability in most of the histologic outcome measures. For example, the older UM-HET3 controls had ACS scores of 6.1±5.8 (mean±SD) and Saf O scores of 6.8± 5.6. Nevertheless, 17-αestradiol mice had larger areas and widths of subchondral bone compared to controls, and dwarf mice had less subchondral bone area and width and less articular cartilage necrosis than non-dwarf controls.

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“…However, αE2 also produces appreciable uterotrophic effect in OVX rodents, as we show here in agreement with others. 18,19 Therefore, confinement of the action of this estrogen into the brain is highly desirable to avoid unwanted hormonal impact on the periphery. This is even more pressing in the context of translational research, as most estrogen-responsive maladies require long-term treatments that bring about critical consideration for safety and efficacy, highlighting thereby the need for brain-selective neurotherapy when proposing the use of αE2 as a preventative and/or curative agent.…”

mentioning

confidence: 99%

10β,17α-Dihydroxyestra-1,4-dien-3-one: A Bioprecursor Prodrug Preferentially Producing 17α-Estradiol in the Brain for Targeted Neurotherapy

Prókai-Tátrai

Nguyen

Prókai

2018

ACS Chem. Neurosci.

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Uterotrophic effect of 17α-estradiol, the C17 epimer of the main human estrogen 17β-estradiol, was shown to manifest in animal models at doses lower than those necessary for central outcome raising concerns about its potential to treat maladies of the central nervous system. We introduce here 10β,17α-dihydroxyestra-1,4-dien-3-one (α-DHED) that acts as a bioprecursor prodrug producing 17α-estradiol with remarkable selectivity to the brain and, therefore, without appreciable exposure of the periphery to the parent steroid. This distinguishing feature of α-DHED is shown by using an estrogen-responsive mouse model with complementary LC-MS/MS measurement of drug contents in target tissues. Our data warrant further research to fully establish the potential of α-DHED for a safe and efficacious 17α-estradiol-based neurotherapy.

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During development, 17alpha-estradiol is a potent estrogen and carcinogen.

Abstract: 577-581 (1997)

Cited by 14 publications

References 22 publications

Long-Term Effects of Neonatal Exposure to Hydroxylated Polychlorinated Biphenyls in the BALB/cCrgl Mouse

Long-Term Effects of Neonatal Exposure to Hydroxylated Polychlorinated Biphenyls in the BALB/cCrgl Mouse

Naturally occurring osteoarthritis in male mice with an extended lifespan

10β,17α-Dihydroxyestra-1,4-dien-3-one: A Bioprecursor Prodrug Preferentially Producing 17α-Estradiol in the Brain for Targeted Neurotherapy

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