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Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati Medical School (N.G.B., D.L.A., N.B.J.), Cincinnati, Ohio 45267; and the Department of Obstetrics and Gynecology, Indiana University School of Medicine (R.S., R.M.B.), Indianapolis, Indiana 46202
Address all correspondence and requests for reprints to: Dr. Nira Ben-Jonathan, Department of Cell Biology, University of Cincinnati Medical School, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0521.
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Abstract |
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BPA increased PRL gene expression, release, and cell proliferation in anterior pituitary cells albeit at a 1000- to 5000-fold lower potency than estradiol. On the other hand, BPA had similar efficacy to estradiol in inducing hyperprolactinemia in estrogen-sensitive Fischer 344 (F344) rats; Sprague Dawley (SD) rats did not respond to BPA. Posterior pituitary cells from estradiol- or BPA-treated F344 rats strongly increased PRL gene expression upon coculture with GH3 cells stably transfected with a reporter gene. Similar to estradiol, BPA induced ERE activation in transiently transfected anterior and posterior pituitary cells.
We conclude that: a) BPA mimics estradiol in inducing hyperprolactinemia in genetically predisposed rats; b) the in vivo action of estradiol and BPA in F344 rats is mediated, at least in part, by increasing PRL regulating factor activity in the posterior pituitary; c) BPA appears to regulate transcription through an ERE, suggesting that it binds to estrogen receptors in both the anterior and posterior pituitaries. The possibility that BPA and other xenoestrogens have adverse effects on the neuroendocrine axis in susceptible human subpopulations is discussed.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, BPA has two unsaturated
phenol rings, but otherwise it has little structural homology with
estradiol. It should be noted, however, that BPA and diethylstilbestrol
(DES), a synthetic substance with potent estrogenic activity, are
structurally similar. Polycarbonates are produced by condensing BPA to
form the carbonate linkages of the polymer (3). Because of superior
stability, toughness, and pliability, BPA-based epoxy resins are used
in many consumer products, including inner coating of food cans, dental
composites, and drug delivery systems. Although normally resilient, the
carbonate linkages can hydrolyze at high temperatures and release BPA.
BPA can also be liberated from incompletely polymerized epoxy resins
(3).
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The estrogenic activity of BPA was accidentally discovered. After reporting that yeast produced estrogens (6), the authors realized that the estrogenic substance in the conditioned media had leached from polycarbonate flasks during autoclaving of water (7). The substance was purified by HPLC and identified by mass spectrometry as BPA. When incubated with the estrogen-responsive MCF-7 breast cancer cells, BPA induced progesterone receptors, competed with tamoxifen in binding to the estrogen receptor and promoted cell proliferation (7). However, the potency of BPA was 3–4 orders of magnitude lower than that of estradiol.
Most studies to date focused on putative carcinogenic effects of xenoestrogens, using primarily in vitro systems, while neglecting their potential impact on the neuroendocrine axis. The pituitary lactotroph is a well characterized estrogen-responsive cell (8, 9). Estrogens can affect PRL release by acting directly on the lactotrophs (10, 11), or indirectly via hypothalamo-pituitary factors that regulate the lactotrophs. These include dopamine, the primary PRL inhibiting factor (12, 13), and PRL regulating factor (PRF) from the posterior pituitary (14). PRF, the structure of which is yet unknown, is produced by a subset of intermediate lobe cells (15) and is the most potent inducer of PRL gene expression (16). PRF-producing cells are likely targeted by estrogens because an intact posterior pituitary is necessary for mediating estrogen-induced surges of PRL (17, 18).
The overall objective of these studies was to examine the effects of BPA on PRL release in vitro and in vivo. For the in vitro system, we used both primary rat anterior pituitary cells and GH3 cells, a somatomammotroph cell line. For the in vivo system, we used two strains of rats: Fischer 344 (F344) and Sprague Dawley (SD). The inbred F344 rat is exquisitively sensitive to exogenous estrogens that rapidly induce hyperprolactinemia and formation of prolactinomas (19, 20). The SD rat, like other rat strains, responds to estrogens with a moderate rise in plasma PRL levels and does not readily form prolactinomas (21, 22).
The specific objectives were to: a) compare the potency of estradiol and BPA in increasing PRL gene expression and release in vitro; b) determine whether BPA stimulates PRL release in vivo; c) examine whether the stimulation of PRL release by estrogens is mediated, in part, by increasing PRF activity in the posterior pituitary; and d) investigate whether BPA regulates transcription in either anterior or posterior pituitary cells through the estrogen response element (ERE).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Estimation of the release rates of E2 and BPA from
SILASTIC capsules
Because there is no established assay for measuring BPA in body
fluids, we compared the release rates of estradiol and BPA under
simulated in vitro conditions. SILASTIC capsules filled with
crystalline estradiol or BPA were incubated in PBS for 3 days at 37 C.
Daily aliquots were fractionated on reversed phase HPLC, eluted
isocratically with acetonitrile-water (40:60) and monitored at 254 nm,
as described (7). Quantitation was based on peak height. The results
showed that BPA and estradiol diffused from the capsules at the
approximate rates of 40–45 µg/day and 1.2–1.5 µg/day,
respectively.
Pituitary cell cultures
GH3 cells were maintained in F-10 media supplemented
with 15% horse serum and 2.5% FBS (Life Technologies, Grand Island,
NY) and were plated in protamine precoated 96-well plates (NUNC,
Copenhagen, Denmark) at 2.5 x 104 cells/well as
described (23). The cells were first incubated for 48 h in phenol
red-free, serum-free media (SFM) composed of DMEM/F-10 (50/50; vol/vol)
and supplemented with 1% ITS + Premix (Collaborative Research,
Bedford, MA) and penicillin/streptomycin and then incubated with the
test substances for 7 days. Stock solutions of BPA, E2 or
testosterone (T; Sigma) were made in ethanol and serially diluted in
SFM; final ethanol concentration was 0.001% or less. Media aliquots
were analyzed in duplicate for PRL by RIA. At different times during
culture, cell number in parallel plates was estimated using the MTT
optical density method (15). Anterior pituitaries, removed from OVEX
F344 rats, were trypsinized and the cells plated as above at 2.5
x 104 cells/well. After 4 days in SFM, the cells were
washed and incubated with different concentrations of E2 or
BPA for 3 days. Media aliquots were analyzed in duplicate for PRL.
Stimulation of PRL gene expression using stably transfected
GH3 cells
GH3 cells were transfected by electroporation with 5
µg PRL/luciferase plasmid containing 2.5 kb of the 5' flanking region
of the rat PRL gene placed upstream of the luciferase coding sequence
(a gift from Dr. R. Maurer, Oregon Health Sciences University) and 0.5
µg pcDNA3 neomycin expression vector (Invitrogen, San Diego, CA).
Positive clones were selected using 300 µg/ml geneticin (G418;
Promega, Madison, WI), and the resulting stably transfected cells were
maintained in 50 µg/ml of G418. The GH3/luc
cells were plated at 2.5 x 104 cells/well and
preincubated in SFM for 48 h. The cells were then incubated with
E2 (1 pM), BPA (1 nM) or TRH (1
nM) for 8 or 24 h. Luciferase activity (designating
induction of the PRL promoter) was determined in cell lysate by
luminometry (16).
Determination of PRF activity using a coculture approach
PRF activity was determined by a bioassay that measures the
ability of posterior pituitary cells to increase PRL gene expression
when cocultured with the GH3/luc cells.
Posterior pituitaries (neurointermediate lobes) were removed from OVEX
F344 and SD rats pretreated for 3 days with E2 or BPA as
described above. The cells were dispersed with trypsin, plated at
1 x 104 cells/well and incubated for 4 days in SFM.
The GH3/luc cells, preincubated for 48 h in
SFM, were then added at 2 x 104 cells/well, and
cocultured with the posterior pituitary cells for 24 h. Luciferase
activity, determined in cell lysate by luminometry as above, was
normalized for cell density that was determined in parallel plates
using the MTT assay.
Determination of estrogen receptor expression in the pituitary
gland by RT-PCR
Anterior and posterior pituitaries were pooled from 2–3 OVEX
F344 and SD rats. Total RNA was isolated using Tri-Reagent (Molecular
Research Center, Cincinnati, OH), and 5 µg were reverse transcribed
using SuperSript II reverse transcriptase (Life Technologies, Grand
Island, NY) and random hexamers. For the PCR reaction, 10% of the RT
products were used. The samples contained intron-spanning primers for
either the ligand binding domain of the estrogen receptor gene (ER-1
5'-GCTCCTAACTTGCTCTTGGACA-3' and ER-2
5'-ATCTCCAGCA-GCAGGTCATAGA-3'), or for the POMC gene (MP-2
5'-TCCTGCTTCAGACCTCCATAGA-3' and MP-3 5'-GGAAGTGACCCATGACGTACTT-3'), a
marker for intermediate lobe melanotrophs. All PCR reactions also had
primers for ribosomal protein L19 (RPL19–1 5'-AGTATGCTTAGGCTACAGAAG-3'
and RPL19–2 5'-TTCCTTGGTC-TTAGACCTGCG-3'), a housekeeping gene
serving as an internal standard. Expected product sizes are 500, 415,
and 209 bp for RPL19, ER, and POMC, respectively. PCR reactions were
denatured at 94 C for 30 sec, annealed at 57 C for 30 sec, and extended
at 72 C for 30 sec for 25 cycles. Products were separated on a 1.5%
agarose gel containing ethidium bromide, and the photograph was scanned
and analyzed using Scion Image software. The number of cycles and
annealing and extension temperatures were optimized, resulting in a
linear relationship between band density and RNA amounts (data not
shown). Band densities for ER and POMC were corrected for those for
RPL19.
Transient transfection of anterior and posterior pituitary cells
with ERE/luciferase reporter gene
Anterior and posterior pituitary cells from OVEX F344 rats were
plated in 24 well plates at 6–7 x 104 cells/well,
with 3–4 wells per treatment, and cultured for 4 days in SFM. Using
calcium phosphate precipitation (Life Technologies) the cells were
cotransfected with 5 µg ERE/luciferase plasmid, containing a single
Xenopus vitellogenin A2 ERE sequence (GGTCACAGTGACC) placed 5' to a
minimal TK promoter driving the expression of the luciferase gene (a
gift from Dr. E. Holler, Regnsburg, Germany), and 0.5 µg
CMV-ß-galactosidase plasmid. After 18 h, media were changed and
the cells incubated with E2 (10 nM) or BPA (1
µM) for 24 h. Luciferase activity was normalized for
ß-gal activity, determined using Galacto-Lite (Tropix, Bedford,
MA).
Data analysis
Data were analyzed by analysis of variance, followed by
Dunnett’s test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, as little as 1 pM estradiol stimulated
PRL release, exhibiting dose dependency up to 1 nM. The
magnitude of release in response to estradiol was not large, however,
and even at 10 nM (data not shown) the rise in PRL did not
exceed 2.5-fold. Like estradiol, BPA increased PRL release in a
dose-dependent manner, but at a 1000- to 5000-fold lower potency.
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, left panel). The effect of BPA on
cell proliferation was examined next. Within 3–5 days, cell number
increased 50–60% in response to estradiol or BPA whereas testosterone
was ineffective (Fig. 3, right panel). Because
GH3 cells are quiescent without serum, the mitogenic
effects of both compounds is significant, albeit small.
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, luciferase activity increased 1.5- to 2.5-fold
in response to either estradiol or BPA; higher doses of either compound
did not further increase PRL promoter activity (data not shown). Note
that 1 nM TRH, a well characterized inducer of the PRL
gene, caused a 6- to 8-fold rise in PRL gene expression, whereas
estradiol induced only 2-fold elevation. This suggests that the overall
effect of estrogenic compounds may involve both direct and indirect
effects on PRL synthesis and release.
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, basal serum PRL levels were 40 and 25 ng/ml in F344
and SD rats, respectively. Within 3 days, estradiol increased serum PRL
levels 10-fold in F344 rats (P < 0.05) but only 3-fold
in SD rats (P < 0.5). BPA increased serum PRL levels
7- to 8-fold over controls in F344 rats (P < 0.05) and
was without effect in SD rats. As evident in Fig. 6, estradiol doubled the anterior pituitary weight in F344 rats within 3
days of treatment (P < 0.05) but caused no significant
increase in pituitary weight of SD rats. Unlike its marked effect on
PRL release in F344 rats, BPA did not alter anterior pituitary weight
in either F344 or SD rats.
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). The stimulation by cells harvested
from estradiol- or BPA-pretreated F344 rats was 15- to 17-fold
(P < 0.05), whereas PRF activity in posterior
pituitary cells from SD rats was unchanged by the estrogens. Note that
the estrogen-induced PRF activity was retained by the cells after
several days in culture.
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).
The estrogen receptors were strongly expressed in the anterior
pituitary with a significantly lower expression in the posterior
pituitary, possibly due to the scarcity of PRF-producing cells. As
expected, POMC expression was much higher in the posterior than
anterior pituitaries.
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, like estradiol, BPA stimulated ERE-dependent
gene expression, suggesting its binding to estrogen receptors in both
tissues.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data show that BPA mimicked estradiol in inducing PRL gene expression, release, and cell proliferation in both primary anterior pituitary cells and GH3 cells. Similar to its action on MCF-7 cells (4, 5, 7), the potency of BPA in vitro was 1000- to 5000-fold lower than that of estradiol. In contrast, BPA was rather effective in stimulating PRL release in vivo, albeit only in F344 rats. The discrepancy between the efficacy of BPA in vitro and in vivo could be due to a combination of factors. First, under simulated in vitro conditions, BPA diffused from the capsules 30–35 times faster than estradiol; this alone, however, cannot explain its increased efficacy in vivo. Second, the pharmacokinetics of BPA may differ from that of estradiol because of higher resistance to degradation, lesser binding to sex-hormone binding proteins, or retention in fat tissues. All of these possibilities should be examined. Third, BPA in vivo may form metabolites, e.g. 5-hydroxy bisphenol and bisphenol o-quinone (24), that are either more active than BPA or synergize with it. As reported recently, combinations of two weak xenoestrogens can be 100 to 1000 times as potent in activating estrogen receptors as each substance alone (25).
We also explored the mechanism underlying the estrogen-sensitivity of
F344. Previous reports suggested that the genetic susceptibility of
F344 rats to estrogens resides in the pituitary because uterine growth
in response to estrogen is normal (19). Furthermore, only pituitaries
from F344, but not other strains, increased in size when grafted to the
kidney capsule of estrogen-treated recipients (19). Other reports
suggested increased neovascularization in the pituitary gland (26) and
elevated production of basic fibroblast growth factor in F344 rats in
response to estrogens (21). The present data confirmed rapid induction
of hyperprolactinemia in F344, but not SD, rats by estrogens. This
could be due either to altered estrogen receptors and/or
estrogen-responsive gene(s) that affect the lactotrophs in F344 rats.
Our results suggest that while functional estrogen receptors are
present in both the anterior and posterior pituitaries (Fig. 9
), there
were no apparent differences in their expression between F344 and SD
rats (Fig. 8). Still, the difference between the rat strains could be
attributed to the presence of estrogen receptor splice variants (27) or
estrogen receptor ß (28). We have preliminary evidence that both the
anterior and posterior pituitaries express a truncated estrogen
receptor product (TERP) as well as estrogen receptor ß. These
findings are presently being confirmed and expanded. Alternatively, the
difference between the rat strains could reside in factors downstream
of the receptor, e.g. coactivators, repressors, or sequence
and binding affinity of ERE on target genes. It would be of interest to
further investigate these possibilities.
The coculture data clearly show that estrogens increase PRF activity in
F344 rats. We previously reported that PRF is produced by a
subpopulation of intermediate lobe cells (15, 29), is distinct from
other PRL secretagogues (30, 31), and is a strong inducer of the PRL
gene (16, 32). Further, we suspected that PRF-producing cells are
targeted by estrogens because an intact posterior pituitary is
necessary for mediating the acute estradiol-induced rise in PRL (17)
and for generating the full pattern of the PRL surge on proestrus (18).
This notion was supported by Frawley et al., reporting that
estrogen induced a mammotropic factor (presumably 
MSH) that rapidly
recruited additional PRL secretors into the secretory pool (33).
Further, the posterior pituitary expresses estrogen receptors (34 and
Fig. 8), and like the uterus, estrogen induces c-fos
expression in this tissue (35).
Although basal PRF activity was similar in both rat strains (Fig. 7),
pretreatment with estradiol or BPA increased PRF activity only in
posterior pituitary cells from F344 rats. This suggests that the
estrogen sensitivity of F344 rats is attributed, at least in part, to
increased responsiveness of PRF-producing cells to estrogens. Because
the structure of PRF is yet unknown, identification of PRF cells awaits
the sequencing of PRF and generation of cellular and molecular probes.
Of interest, BPA stimulated PRL release but did not increase the
pituitary weight in F344 rats (Fig. 6). This suggests that BPA does not
mimic all of the in vivo actions of estradiol. Indeed,
tissue-selective estrogenic activity has been reported for several
estrogenic compounds (36).
Because humans are exposed to significant amounts of BPA through canned food and dental devices (4, 5), the present findings may have implications to human hyperprolactinemia. Although oral contraceptives do not normally induce hyperprolactinemia (37), women who used oral contraceptives for menstrual irregularities rather than for prevention of pregnancy, have a 7- to 8-fold higher incidence of prolactinomas (38). This suggests that exogenous estrogens may stimulate incipient prolactinomas to grow or are more mitogenic in women with reproductive disorders. Whether this is related to the expression of multiple splice variants of the estrogen receptor by human prolactinomas (39) remains to be determined.
In conclusion, we demonstrated estrogen-mimicking activity of BPA both in vitro and in an animal model. BPA and other xenoestrogens constitute an unsuspected source of compounds capable of altering the natural hormonal balance. Perhaps there is a human homolog to the F344 rat, i.e. only individuals with altered estrogen receptors and/or estrogen responsive genes are predisposed to the effects of xenoestrogens. To better evaluate potential hazards posed by such compounds to human health, more information is needed on their exposure, pharmacokinetics, synergistic interactions, and ability to activate a variety of estrogen-responsive genes.
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Acknowledgments |
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Footnotes |
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Received November 11, 1996.
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References |
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-melanocyte stimulating hormone is a mammotrophic factor released by
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 S. Sekiguchi, G. Asano, M. Suda, and T. Honma Influence of 2-bromopropane on reproductive system--Short-term administration of 2-bromopropane inhibits ovulation in F344 rats Toxicology and Industrial Health, August 1, 2000; 16(7-8): 277 - 283. [Abstract] [PDF]
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D. M. Sheehan Activity of Environmentally Relevant Low Doses of Endocrine Disruptors and the Bisphenol A Controversy: Initial Results Confirmed Experimental Biology and Medicine, June 1, 2000; 224(2): 57 - 60. [Full Text]
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 T. Iguchi and T. Sato Endocrine Disruption and Developmental Abnormalities of Female Reproduction Integr. Comp. Biol., June 1, 2000; 40(3): 402 - 411. [Abstract] [Full Text] [PDF]
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S. Kwon, D. B. Stedman, B. A. Elswick, R. C. Cattley, and F. Welsch Pubertal Development and Reproductive Functions of Crl:CD BR Sprague-Dawley Rats Exposed to Bisphenol A during Prenatal and Postnatal Development Toxicol. Sci., June 1, 2000; 55(2): 399 - 406. [Abstract] [Full Text] [PDF]
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 J. Ashby Validation of In Vitro and In Vivo Methods for Assessing Endocrine Disrupting Chemicals Toxicol Pathol, May 1, 2000; 28(3): 432 - 437. [Abstract] [PDF]
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W.-C. Song and M. H. Melner Editorial: Steroid Transformation Enzymes as Critical Regulators of Steroid Action in Vivo Endocrinology, May 1, 2000; 141(5): 1587 - 1589. [Full Text] [PDF]
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B. T. Akingbemi, R.-S. Ge, G. R. Klinefelter, G. L. Gunsalus, and M. P. Hardy A Metabolite of Methoxychlor, 2,2-Bis(p-Hydroxyphenyl)-1,1,1-Trichloroethane, Reduces Testosterone Biosynthesis in Rat Leydig Cells Through Suppression of Steady-State Messenger Ribonucleic Acid Levels of the Cholesterol Side-Chain Cleavage Enzyme Biol Reprod, March 1, 2000; 62(3): 571 - 578. [Abstract] [Full Text]
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H. Inadera, T. Sekiya, T. Yoshimura, and K. Matsushima Molecular Analysis of the Inhibition of Monocyte Chemoattractant Protein-1 Gene Expression by Estrogens and Xenoestrogens in MCF-7 Cells Endocrinology, January 1, 2000; 141(1): 50 - 59. [Abstract] [Full Text] [PDF]
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 E. Y.K. FUNG, N. O. EWOLDSEN, H. A. ST. GERMAIN JR., D. B. MARX, C.-L. MIAW, C. SIEW, H.-N. CHOU, S. E. GRUNINGER, and D. M. MEYER PHARMACOKINETICS OF BISPHENOL A RELEASED FROM A DENTAL SEALANT J Am Dent Assoc, January 1, 2000; 131(1): 51 - 58. [Abstract] [Full Text] [PDF]
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T. E. Stoker, C. L. Robinette, B. H. Britt, S. C. Laws, and R. L. Cooper Prepubertal Exposure to Compounds That Increase Prolactin Secretion in the Male Rat: Effects on the Adult Prostate Biol Reprod, December 1, 1999; 61(6): 1636 - 1643. [Abstract] [Full Text]
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N. A. Mitchner, C. Garlick, R. W. Steinmetz, and N. Ben-Jonathan Differential Regulation and Action of Estrogen Receptors {alpha} and {beta} in GH3 Cells Endocrinology, June 1, 1999; 140(6): 2651 - 2658. [Abstract] [Full Text]
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F. Olea-Serrano, P. Lardelli-Claret, A. Rivas, A. Barba-Navarro, and N. Olea Inadvertent exposure to xenoestrogens in children Toxicology and Industrial Health, February 1, 1999; 15(1-2): 152 - 159. [Abstract] [PDF]
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T. Colborn and P. Short Pesticide use in the U.S. and policy implications: A focus on herbicides Toxicology and Industrial Health, February 1, 1999; 15(1-2): 241 - 276. [Abstract] [PDF]
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G. G. J. M. Kuiper, J. G. Lemmen, B. Carlsson, J. C. Corton, S. H. Safe, P. T. van der Saag, B. van der Burg, and J.-A. Gustafsson Interaction of Estrogenic Chemicals and Phytoestrogens with Estrogen Receptor {beta} Endocrinology, October 1, 1998; 139(10): 4252 - 4263. [Abstract] [Full Text] [PDF]
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 F. J. M. Verhagen, H. J. Swarts, J. B. P. A. Wijnberg, and J. A. Field Biotransformation of the Major Fungal Metabolite 3,5-Dichloro- p-Anisyl Alcohol under Anaerobic Conditions and Its Role in Formation of Bis(3,5-Dichloro-4-Hydroxyphenyl)methane Appl. Envir. Microbiol., September 1, 1998; 64(9): 3225 - 3231. [Abstract] [Full Text]
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N. A. Mitchner, C. Garlick, and N. Ben-Jonathan Cellular Distribution and Gene Regulation of Estrogen Receptors {alpha} and {beta} in the Rat Pituitary Gland Endocrinology, September 1, 1998; 139(9): 3976 - 3983. [Abstract] [Full Text] [PDF]
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R. Steinmetz, N. A. Mitchner, A. Grant, D. L. Allen, R. M. Bigsby, and N. Ben-Jonathan The Xenoestrogen Bisphenol A Induces Growth, Differentiation, and c-fos Gene Expression in the Female Reproductive Tract Endocrinology, June 1, 1998; 139(6): 2741 - 2747. [Abstract] [Full Text] [PDF]
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 J. I. Macgregor and V. C. Jordan Basic Guide to the Mechanisms of Antiestrogen Action Pharmacol. Rev., June 1, 1998; 50(2): 151 - 196. [Abstract] [Full Text] [PDF]
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F. S. Vom Saal, P. S. Cooke, D. L. Buchanan, P. Palanza, K. A. Thayer, S. C. Nagel, S. Parmigiani, and W. V. Welshons A Physiologically Based Approach To the Study of Bisphenol a and Other Estrogenic Chemicals On the Size of Reproductive Organs, Daily Sperm Production, and Behavior Toxicology and Industrial Health, January 1, 1998; 14(1-2): 239 - 260. [Abstract] [PDF]
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R. Hnasko, S. Khurana, N. Shackleford, R. Steinmetz, M. J. Low, and N. Ben-Jonathan Two Distinct Pituitary Cell Lines from Mouse Intermediate Lobe Tumors: A Cell that Produces Prolactin-Regulating Factor and a Melanotroph Endocrinology, December 1, 1997; 138(12): 5589 - 5596. [Abstract] [Full Text] [PDF]
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D. Feldman M.D. Editorial: Estrogens from Plastic--Are We Being Exposed? Endocrinology, May 1, 1997; 138(5): 1777 - 1779. [Full Text] [PDF]
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D. L. Allen, N. A. Mitchner, T. E. Uveges, K. P. Nephew, S. Khan, and N. B. Jonathan Cell-Specific Induction of c-fos Expression in the Pituitary Gland by Estrogen Endocrinology, May 1, 1997; 138(5): 2128 - 2135. [Abstract] [Full Text]
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