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* Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA; and
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, 06520 USA
1Correspondence: Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St., New Haven, Connecticut 06520 USA. E-mail: hugh.taylor{at}yale.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: genes • homeobox • teratogens • fetal development • estrogens
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. However, in
1971 DES was banned from being used during pregnancy after the
demonstration of an increase in adenocarcinoma of the vagina in young
women exposed to the drug in utero (2)
.
Subsequently, it has been demonstrated that women exposed in
utero have a high incidence of anatomic abnormalities of the
genital tract that adversely affect their reproductive capacity.
Various estrogens have been shown to alter stromal epithelial
interactions and result in anomalies of the reproductive tract, but the
molecular mechanisms by which estrogens alter the development of the
müllerian tract are unknown (3
4
5)
.
We have previously demonstrated that Hox genes are involved in
determining the developmental identity of segments of the reproductive
tract (6)
. The nested expression of Hox genes impart
positional identity along multiple developing axis, representing a
universal molecular mechanism by which spatial distinctions can be
encoded: the linear arrangement of these genes on a chromosome is
paralleled by their temporal and spatial expression patterns. Ectopic
expression of HOX genes can cause homeotic transformation in which body
structures are duplicated in abnormal positions or replaced along the
anterior-posterior body axis. The developing müllerian system
represents such an axis. Hoxa9, Hoxa10, Hoxa11, and Hoxa13 are
expressed along the axis of the previously undifferentiated
paramesonephric duct in segments that give rise to oviducts, uterus,
uterine cervix, and upper vagina, respectively. Targeted mutation of
several posterior HOX genes that are paralogs of the
Drosophila abdominal B (AbdB) gene results in defects in the
female reproductive tract of mice, suggesting that alterations in HOX
gene expression could be a basis for DES-related anomalies
(7
8
9
10
11
12)
. This Hox axis found in the mouse reproductive
tract is conserved in the human reproductive tract as evidenced by an
equivalent expression pattern of human HOX genes (6)
. HOX
gene expression in the developing reproductive tract of the mouse may
be a suitable model to evaluate the effects of potentially harmful
drugs, such as DES, on human development.
HOX genes expressed in the developing reproductive tract demonstrate
persistent adult expression (6)
. Insults to the developing
müllerian organs in utero may be reflected in the
adult pattern of HOX gene expression. We have recently shown that
HOXA10 and HOXA11 expression is directly regulated by 17ß-estradiol
in humans (13
, 14)
. In this study, we ask whether exposure
in utero to the nonsteroidal estrogen DES alters the
expression of these HOX genes in the developing reproductive tract,
providing a molecular mechanism by which DES produces congenital
anomalies.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Probe preparation
Plasmids used for probe preparation were a generous gift from E.
Boncinelli. pGEM plasmids containing sequence from the 3' untranslated
region of human HOXA9, HOXA10, HOXA11, and HOXA13 were linearized with
EcoRI or HindIII (New England Biolabs, Beverly,
Mass.), ethanol precipitated, and individually used as a template for
generation of riboprobes. Radiolabeled RNA probes were generated by
in vitro transcription using the Promega Riboprobe Kit
(Madison, Wis.). Sense and antisense probes were generated using the
appropriate RNA polymerase (T7 or SP6) and labeled with
alpha-[33P] or [32P]
UTP (Amersham, Arlington Heights, Ill.).
Northern blot analysis
Tissues or cultured cells were homogenized in 4 M guanidinium
thiocyanate, 25 mM sodium citrate (pH 7.0), 0.5% sarkosyl, and 0.1 M
2- mercaptoethanol. Total RNA was size-fractionated on a 1%
agarose-0.66 M formaldehyde gel, blotted to nitrocellulose, and
hybridized with a [32P]-labeled riboprobe
prepared as described above. Hybridization was performed overnight at
60°C in 50% formamide, 1x SSC, 5x Denhardt’s reagent, 0.2% tRNA,
and [32P]-labeled riboprobe at 2 x
106 cpm/ml. The filter was washed twice at 68°C for 30
min in 0.1x SSC and 0.1% sodium dodecyl sulfate. Kodak (Rochester,
N.Y.) X-Omat AR film was exposed overnight at -70°C.
In situ hybridization
In situ hybridization was performed with both sense
and antisense [33P]-labeled riboprobes. Tissue
was fixed in 4% paraformaldehyde, cryoprotected in 30% sucrose, and
embedded in OCT compound (Miles, Elkhart, Ind.). Ten micrometer frozen
sections were obtained and mounted on Vectabond-coated slides (Vector
Laboratories, Burlingame, Calif.). Prior to use, sections were treated
with 0.2 M HCl, Pronase (0.16 mg/ml), and 0.026 M acetic anhydride,
then dehydrated. Tissue sections were hybridized overnight with 3 x 106 cpm of each probe in 0.25 M NaCl,
0.01 M Tris-HCl (pH7.5), 0.01 M NaP04 (pH 6.8), 5
mM EDTA, Ficoll 400 (0.02%), polyvinylpyrolidone (0.02%), bovine
serum albumin (BSA) fraction V (0.02%), 50% formamide, 12.5% dextran
sulfate, yeast tRNA (1.25 mg/ml), and 10 mM DTT. Hybridization was
performed in a humidified chamber for 16 h at 50°C. Slides were
treated with Rnase A at 37°C and then washed 16 h in 0.25 M
NaCl, 0.01 M Tris-Cl (pH 7.5), 0.01 M NaP04 (pH
6.8), 5 mM EDTA, Ficoll 400 (0.02%), polyvinylpyrolidone (0.02%), BSA
fraction V (0.02%), and 50% formamide. Slides were dehydrated and
dried, and autoradiographs were obtained before being dipped in Ilford
K5D (Mobberley, U.K.) emulsion. Exposure was carried out at 4°C for 7
to 12 days and slides were developed with Kodak D-19. Slides were
counterstained with hematoxylin and eosin. Representative darkfield and
brightfield photomicrographs were taken at 20x and 100x magnification
respectively, on an Olympus (Lake Success, N.Y.) microscope with Kodak
Ectachrome film.
Cell culture
Ishikawa and SKOV3 cells were maintained in phenol red-free
Eagle’s minimum essential medium containing 10% (v/v) charcoal
stripped fetal bovine serum and supplemented with penicillin (100
µg/ml), glutamine (2 mM), and sodium pyruvate (1 mM). HeLa cells were
maintained in McCoy’s media modified as above. Confluent monolayers
were maintained in serum-free media for 24 h and subsequently
treated with 17ß-estradiol (5x10-8 M) or DES
(5x10-8 M). HeLa cells were first transfected
with a full-length human estrogen receptor expression construct (a gift
of Richard Hochberg). A 25 cm2 cellular monolayer
was transfected with 3 ml of a solution containing 16 µg/ml of
pCMV5/hER and 40 µg/ml liposomes (lipofectamine) in
phosphate-buffered saline. Cells were maintained in McCoy’s media an
additional 24 h prior to treatment with 17ß-estradiol or DES.
Estrogen and progesterone receptor status was verified in each cell
line by enzyme-linked immunoassay according to the manufacturer’s
instructions (Abbott, Wiesbaden, Germany).
Statistical analysis
The autoradiographic bands were quantified using a laser
densitometer (Molecular Dynamics Inc., Sunnyvale, Calif.). Each band
was normalized to the value obtained from the same lane hybridized to
G3PDH. Data were analyzed using analysis of variance (ANOVA).
Statistical significance was defined as P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 16)
. These alterations resemble those of affected women. Five
DES-treated mice delivered litters of reduced size, whereas all five of
the mice injected with a control delivered litters of normal size. At 2
wk of age, the female offspring were killed and reproductive tracts
were dissected. DES-treated offspring exhibited typical reproductive
tract anomalies. In situ hybridization was performed with
33P-labeled riboprobes complementary to each of
the 3' untranslated regions of Hoxa9, Hoxa10, Hoxa11, and Hoxa13.
Figure 1
shows darkfield photomicrographs of the results.
|
The reproductive tracts of the mice exposed to DES are abnormally
shaped reflecting the expected morphological changes found after DES
exposure. Expression of Hoxa9 is localized to the oviducts in the
control. In DES-exposed mice, Hoxa9 expression is found in a more
caudal distribution. Hoxa9 is now expressed at appreciable levels in
the uterus (Fig. 1)
and expression is absent in the oviducts.
Similarly, peak Hoxa10 expression is shifted to the base of the uterus
from its normal expression pattern throughout the uterus. DES exposure
in utero has resulted in the more caudal expression of
Hoxa10. Hoxa10 expression is significantly decreased in its normal
location of expression, the cranial aspect of the uterus (Fig. 1)
.
Hoxa11 expression is dramatically decreased throughout its normal range
of expression in the uterus. Even at exposures of up to 12 days (shown
here, 12 day exposure), Hoxall expression remains dramatically reduced.
Hoxa13 is normally expressed in the vagina. DES exposure does little to
alter Hoxa13 expression, as far as can be detected by in
situ hybridization. Identical results were seen using tissue
obtained from each of the experimental mice.
In summary, the results of the in situ hybridization show a posterior shift in Hoxa9 and Hoxa10 expression. A similar decrease in the anterior portion of the Hoxa11 expression domain is observed. Expression of the most posterior Hox gene, Hoxa13, is unaltered. DES exposure in utero leads to a persistent posterior shift in the Hox axis of the reproductive tract toward the expression domain of the most posteriorly expressed Hox gene, a13.
High-power brightfield views of tissue sections from DES-exposed mice
after in situ hybridization confirm and localize the above
results as shown in Fig. 2
. We previously defined normal cellular expression in the mouse for each
of these genes (6)
. After DES exposure, Hoxa9 expression
is shifted to a tissue different from that where it is normally
expressed, i.e., from the oviduct to the uterus. To identify which
uterine cells expressed Hoxa9, high-power views were examined. A
control sense probe lacks hybridization (Fig. 2a
). Both
glands and stroma of the uteri obtained from DES-exposed mice
abundantly expressed Hoxa9 (Fig. 2b
). Hoxa9 expression is
absent from its normal location in the epithelium of the oviduct as
demonstrated in Fig. 2c
. High-power views of
photomicrographs obtained after in situ hybridization with a
Hoxa10 probe show Hoxa10 absent from both glands and stroma in the
upper segment of the uterus but normally expressed in the caudal
uterine segment (data not shown). Hoxa11 shows extremely low levels of
expression in the uterus of DES-exposed mice, but the pattern of
expression is unchanged from controls (data not shown). Hoxa13
expression is high in the vagina, its normal location, and is still
found in the surface epithelium as previously demonstrated (Fig. 2d
).
|
To quantify expression, Northern analysis was performed. Tissue was
obtained separately from the oviduct, uterus, and vagina from both
control mice and mice exposed to DES in utero. Five animals
were used for each group. RNA was extracted, size-fractionated, and
hybridized individually to 32P-labeled Hoxa9,
Hoxa10, Hoxa11, and Hoxa13 riboprobes. Densitometry of the resultant
autoradiographs was performed and Hox values were normalized to values
obtained with G3PDH. Results are shown in Fig. 3
. Hoxa9 is normally expressed in the oviduct. Hoxa9 expression is
dramatically decreased in the oviduct of DES-exposed mice. The
expression of other Hox genes remains low in the oviduct of DES-treated
mice, at levels similar to controls (Fig. 3
, first panel). Hoxa9
expression is dramatically increased in the uterus of DES-exposed mice
when compared to controls (Fig. 3
, second panel), confirming and
quantifying the results of the in situ hybridization. Hoxa10
levels are reduced in the uterus, reflecting the posterior shift in
expression seen in the in situ hybridization and loss of
expression from the uterine fundus. Hoxa11 levels are dramatically
decreased.
|
In the vagina (Fig. 3
, third panel), Hox gene expression is only
minimally altered. In controls Hoxa13 is the primary Hox gene expressed
and remains so in DES-treated mice. Hoxa11 levels are increased,
perhaps representing a posterior shift of Hoxall expression to the
vagina, but not at a statistically significant level as detectable in
this study.
DES alters Hox gene expression in human cell culture
To test for applicability of our mouse model to humans, uterine,
cervical, or ovarian cell culture models were used. Hoxa9 is not
normally expressed in the uterus of human or mice (6)
. As
demonstrated above, DES induces Hoxa9 expression in the uterus of mice
in vivo. Expression of the Hox gene most affected in
vivo in mice, Hoxa9, is altered by DES in human uterine cells in
culture. Ishikawa cells, a well-differentiated endometrial
adenocarcinoma cell line that we have previously demonstrated to
express HOXA10 and HOXA11 in response to treatment with 17
ß-estradiol, (13
, 14)
, were treated with DES. Cells were
treated with inert vehicle (control), 17ß-estradiol, or DES, then RNA
extracted with guanidinium thiocyanate/phenol, size fractured on a
formaldehyde gel, transferred to a membrane, and hybridized with a
32P-labeled probe specific to the 3' untranslated
region of HOXA9. Autoradiography and densitometry were performed and
normalized in G3PDH. DES produced a fourfold increase in expression of
HOXA9 as compared to control (Fig. 4
HOXA9 mRNA levels after DES treatment also differed from that of cells
treated with 17 ß-estradiol. Cyclohexaminde pretreatment did not
block the response, indicating DES likely directly regulates HOX gene
expression.
|
HeLa cells, a cervical carcinoma cell line, were used as a model for
the cervix. As demonstrated above, HOXA10 is expressed in the cervix of
DES-exposed mice but not at significant levels in controls. HOXA10
expression does not exceed control levels when HeLa cells are treated
with 17ß-estradiol (Fig. 4B
). Treatment of these cells
with DES expression dramatically increases HOXA10 expression.
SKOV-3 cells were used as a model of ovary. This tissue is not of
müllerian origin and does not normally express HOXA9, HOXA10,
HOXA11, or HOXA13 at high levels. Neither 17ß-estradiol nor DES
induces HOX gene expression in this cell line. Figure 4C
demonstrates a lack of change in HOXA10 expression in response to
treatment with these estrogens. Similarly, there was no change in
expression of HOXA9, HOXA11 or HOXA13 (not shown).
DES produces an increased expression of HOXA9 in a uterine endometrial cell line and an increased expression of HOXA10 in a cervical cell line. These effects mimic the posterior shift in Hox gene expression seen in tissues that correspond to these cell lines. A cell line of reproductive tract origin but not of müllerian origin does not show these effects.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 18)
.
The reproductive tract represents such an axis; differential Hox gene
expression in segments of the undifferentiated paramesonephric duct
leads to development of distinct reproductive organs (6)
.
Alterations of Hox gene expression of the type demonstrated here can be
expected to lead to anomalies in the tissues that depend on their
expression for proper development signals. Typically, the more
posterior Hox genes are phenotypically dominant; they suppress the
expression and function of the more anterior Hox genes, a property
termed posterior prevalence (17)
. The alterations in Hox
gene expression patterns described above represent a posterior shift
from the normal pattern. DES induces a posterior shift in Hoxa10
expression such that much of the uterus expresses less Hoxa10. DES also
decreases Hoxa11 expression throughout the uterus. Hoxa10 and Hoxa11
expression in the uterus likely normally represses Hoxa9 expression.
Decreased levels of expression of Hoxa10 and Hoxa11 may now allow for
the increased Hoxa9 expression levels that are demonstrated after DES
exposure.
The decreased Hoxa9 levels may lead to reduced or altered
differentiation in the pathway leading to the development of the
oviduct. This could account for the abnormal oviducts seen in mice
after DES exposure and the ‘withered’ fallopian tubes seen in women
who were exposed to DES in utero (19)
. Complete
absence of the tubes may not occur because of the redundancy provided
by Hox genes from the Hox B, C, and D clusters.
Similarly, the decreased Hoxa10 and Hoxa11 and increased Hoxa9 expression in the uterus may cause the uterus to develop along a pathway consistent with the tissue normally directed to develop by Hoxa9: the oviduct. Accordingly, the classic T-shaped uterus, seen in up to 70% of women exposed to DES in utero, may represent an oviduct like phenotype. The uterus is narrowed and branches into two tube-like structures, resembling the shape of the letter T rather than a pear-shaped cavity. This shape may represent transformation into an oviduct-like structure. Again, complete transformation to an oviduct may be prevented by the redundancy provided by the other Hox clusters.
These alterations in Hox gene expression represent a posterior shift from the normal pattern. The presence of tissue in more posterior locations is common in women exposed to DES. For example, these women develop vaginal adenosis, which is the development of glandular tissue (normally found in the cervix or uterus) in the vagina. Changes in the reproductive tract seen after DES exposure may represent homeotic transformation typical of that seen with mutation and loss of function of homeotic genes in other species. Typically, Hox gene mutations result in posterior structures taking on the appearance of the next most anterior structure. The changes seen in reproductive anatomy in women after DES exposure are typical of this type of anterior transformation and correlate well with the changes in HOX expression reported above. DES-induced posterior shifts in HOX gene expression lead to anterior transformations of the reproductive tract. These molecular changes may explain the anatomic defects seen in women exposed to DES.
Alterations of Hox gene expressions are a molecular mechanism by which DES-related congenital malformations may occur.
Estrogen regulation of the Hox gene axis of the reproductive tract
Few regulators of the spatial expression patterns of Hox genes are
known (18
, 20
, 21)
; estrogens are novel morphogens capable
of segmental regulation of Hox genes during development. Sex steroids
likely influence the expression levels of, and establish an axis of the
posterior Hox genes, analogous to the role of retinoic acid in
establishing expression patterns of the anterior Hox genes
(22
23
24)
. DES, acting via the estrogen receptor, results
in aberrant HOX gene expression.
Estrogens exert their effects by binding to estrogen receptors, which
act as transcription factors (25
, 26)
. There are two genes
that encode estrogen receptors. Estrogen receptor 
is known to
regulate the differentiation and adult maintenance of reproductive
tissues (27
, 28)
. Estrogen-like agents that bind to the
estrogen receptor are currently used to treat menopause, osteoporosis,
cardiovascular disease, and breast cancer (29
, 30)
.
17ß-Estradiol and DES both bind to the ligand binding domain (LBD) at
the carboxyl terminus of the estrogen receptor. Ligand-dependent
activation of transcription requires interaction with coactivators
(31
, 32)
. The crystal structure of the ER LBD bound to DES
and other estrogens shows that different estrogens induce differential
coactivator binding (33
, 34)
. 17ß-Estradiol and DES
likely have different effects on reproductive tract development because
of different abilities to interact with coactivators necessary for
proper Hox expression. This suggests that Hox gene expression is
regulated by combined ER, coactivator, and estrogen action. DES likely
interferes with the formation of the ER–coactivator complex necessary
for proper tissue specific transcription. The present study provides
evidence that the transcriptional regulation of Hox gene expression is
altered by DES.
Alteration in Hox gene expression persists in the adult
The alteration in Hox gene expression described here persists well
beyond the time of exposure to DES. This observation demonstrates that
altered Hox gene expression may be a potential marker in the adult of
the adverse developmental effects of in utero drug exposure.
DES-related anomalies in women were not noted until those exposed
in utero were young adults. Changes in the expression of Hox
genes is a possible mechanism by which one could test for the ability
of a drug to alter development or discern past exposure to agents that
might alter developmental regulation.
Between 10 and 70% of exposed women demonstrated abnormalities of the
reproductive tract (1)
. Frequency of müllerian
abnormalities is related to the gestational age at the time of exposure
and the total dose of DES received. This variability is also likely due
to differences in detection. An association between clear cell
adenocarinoma of the vagina in women and in utero DES
exposure has been clearly established, yet the mechanism by which DES
leads to carcinogenesis is not understood (2)
. Of those
women exposed to DES in vitro, only ~1 per 1000 develop
vaginal adenocarcinoma. Although vaginal developmental anomalies
(vaginal adenosis) are a common finding in women exposed to DES, clear
cell adenocarcinoma is rare. Factors other than DES are undoubtedly
involved in the etiology of this tumor. The findings of this study
suggest that altered development of the reproductive tract occurs via
altered HOX gene expression. The resultant homeotic transformation of
tissue identity, such as ectopic tissue in the vagina, may then be
susceptible to carcinogenesis. Localization to the cervix may normally
offer protection; exposure via the vagina to carcinogens may make
vaginal adenosis prone to cancer formation. Hormonal carcinogenesis may
be an indirect effect of homeotic transformation during development
rather than a direct effect of DES.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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S. LI, S. D. HURSTING, B. J. DAVIS, J. A. McLACHLAN, and J. C. BARRETT Environmental Exposure, DNA Methylation, and Gene Regulation: Lessons from Diethylstilbesterol-Induced Cancers Ann. N.Y. Acad. Sci., March 1, 2003; 983(1): 161 - 169. [Abstract] [Full Text] [PDF]
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 P. J. Troy, G. S. Daftary, C. N. Bagot, and H. S. Taylor Transcriptional Repression of Peri-Implantation EMX2 Expression in Mammalian Reproduction by HOXA10 Mol. Cell. Biol., January 1, 2003; 23(1): 1 - 13. [Abstract] [Full Text]
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D. Cermik, B. Selam, and H. S. Taylor Regulation of HOXA-10 Expression by Testosterone in Vitro and in the Endometrium of Patients with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 238 - 243. [Abstract] [Full Text] [PDF]
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M. R. Fielden, R. G. Halgren, C. J. Fong, C. Staub, L. Johnson, K. Chou, and T. R. Zacharewski Gestational and Lactational Exposure of Male Mice to Diethylstilbestrol Causes Long-Term Effects on the Testis, Sperm Fertilizing Ability in Vitro, and Testicular Gene Expression Endocrinology, August 1, 2002; 143(8): 3044 - 3059. [Abstract] [Full Text] [PDF]
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