* Comparative Neuroanatomy Laboratory of Ecology Department, University of Calabria, 87030 Arcavacata di Rende-Cosenza, Italy; Animal Biology Department, University of Firenze, 50100 Firenze, Italy
1 To whom correspondence should be addressed at Comparative Neuroanatomy Laboratory, Ecology Department, University of Calabria, Ponte Pietro Bucci, 87030 Arcavacata di Rende, Cosenza, Italy. Tel. +39-984 492973-4 Fax +39-984 492986. E-mail: rm.facciolo{at}unical.it.
Received July 6, 2005; accepted September 8, 2005
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ABSTRACT |
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Key Words: nonpeptide agonists; GABAA receptor; xenoestrogens; cortex; hippocampus; hypothalamus.
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INTRODUCTION |
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From the precise correlation between behavioral and neuronal activities, many neurotransmitter systems such as somatostatin and GABA have been shown to be linked to the predominant estrogen-like BPA effects (Facciolo et al., 2002b). In mammals, somatostatin has been proven to exert a major inhibitory role on growth hormone (GH) secretion, as well as to regulate various neuroendocrine and cognitive functions such as body temperature, satiety, and memory (Lahlou et al., 2004
). At present, five different somatostatin receptor subtypes (sst1-5) have been cloned, and all possess a heptahelical architecture that is typical of the G proteincoupled receptors (Csaba and Dournaud, 2001
). Of the above-mentioned somatostatin receptor subtypes, sst3, which is widely distributed throughout the brain, appears relatively early during development and remains stable throughout adult life; as a consequence, it exerts a key influence on the organization of the central nervous system (CNS) (Thoss et al., 1995
). In this context, the interference of BPA with protein Gcoupled receptors (Ishido et al., 2005
) through the interaction of estrogen receptors (Quesada et al., 2002
), as well as the upregulating effects of estrogens on mRNA expression of sst2,3 (Djordjijevic et al., 1998
) and the co-localization of such somatostatin receptor subtypes to both estrogen and GABA receptors (Arancibia et al., 1997
; Saha et al., 2002
), point to sst3 as a major neuromediating target of BPA-dependent actions.
GABA, the other component co-localized with somatostatin receptor subtypes and estrogen receptors, is also considered an important neuronal receptor capable of mediating the bulk of rapid inhibitory synaptic transmission in the CNS. The functional features of GABAA receptors are determined by heteromeric combinations of subunits encoded by 20 genes: (16), ß(14),
(14),
,
,
,
, and
(12). Recombination of these subunits forms different binding sites that display various affinity states for drugs such as benzodiazepines, barbiturates, convulsants, and neurosteroids (Barnard et al., 1998
). In particular, the
subunit is involved in the assembly of the other subunits, as well as the overall biophysical and pharmacological properties of the GABAA receptor complex (Rudolph et al., 1999
). Because somatostatin receptor subtypes are tightly coupled to this complex, the above
subunit becomes a determing cross-talking element in specific BPA-dependent neurophysiological risks, an event that seems to rely, in an estrogenic fashion, on alterations evoked during early developmental stages in the rat (Facciolo et al., 2002b
).
Thus, it was our intention to determine the type of relationship that is explicated by BPA toward the formation of sst3 mRNA and to understand whether this effect requires the participation of the GABAA receptor subunits. A relationship that was previously demonstrated for the mRNA formation of other important endocrine-disrupting targets such as the arylhydrocarbon receptor, which is involved in the mediation of stressor activities in some GABAergic neurons (Hays et al., 2002
). Moreover, it was interesting to establish a regional specificity of BPAsst3 interactions in specific female brain regions, with particular attention to hypothalamic sites, because somatostatin receptor subtype effects have been reported in areas such as the hypothalamic periventricular nucleus (Simonian et al., 1998
), which in females is highly estrogen-enriched (McEwen, 2002
). In addition, the extrahypothalamic areas, such as the frontoparietal cortex (layer III and V) and the hippocampus, have also been considered in this study because of their elevated densities of estrogen receptors plus their somatostatin receptor subtypedependent role in memory and spatial tasks, as well as sociosexual and neurovegetative functions (Csaba and Dournaud, 2001
).
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MATERIALS AND METHODS |
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Eight days after the beginning of treatment, a different sexually mature Sprague-Dawley male was assigned to each of the eight cages of female rats for 8 days. Pregnant females that subsequently gave birth to all pups successfully were isolated in single stainless-steel cages where they continued to receive the same BPA treatment until weaning, i.e., postnatal day (PND) 23. To minimize litter effects, at birth one female pup per litter was randomly assigned to a new cage (n = 8 pups of the same age) containing a dam of the same BPA treatment group, as follows: higher dose (BPA400) and lower dose (BPA40). Another 16 pups were culled for the OIL group. For this part of the study and throughout, all experimental data refer to the female offspring at PND 7 (n = 12) and at 55 days of age (adults n = 16) of all treatment groups. The animals were decapitated and their brains were quickly removed for in situ hybridization histochemistry and for in vitro quantitative autoradiography studies.
Animal maintenance and all experimental procedures were carried out in accordance with the Guide for Care and Use of Laboratory Animals issued by the European Communities Council Directive of 24 November 1986 (86/609/EEC). Efforts were made to minimize animal suffering and to minimize the number of specimens used.
BPA and sst3 mRNA Levels
In vitro quantitative autoradiography.
In a preliminary phase of the histochemistry, competition autoradiography approaches for sst3 were carried out on some coronal brain sections (two sections per slide; 12-µm-thick) of adult females (n = 4) from the OIL group. For this phase, animals were decapitated and brains were rapidly removed and frozen using powdered dry ice, after which they were stored at 40°C until sectioning at the cryostat and thaw-mounting onto gelatin-coated slides, as previously described (Facciolo et al., 2002b), for further biochemical analyses. Subsequently, brain sections were incubated for 1 h at room temperature in 50 mM Tris HCl, pH 7.4, containing 0.5% bovine serum albumin and 25 pM of 125I-Tyr1-ss-14 (81.4 TBq/mmol; NEN Division) in the presence of different concentrations (1 µM1 pM) of ss-14 and highly specific nonpeptide agonists (L-779,976 and L-796,778) selective for sst2 and sst3 (Rohrer et al., 1998
), respectively, ±1 µM cold ss-14 for nonspecific binding. A somewhat low concentration of the radioligand was preferred because most somatostatinergic actions are mediated via specific membrane-bound high-affinity somatostatin receptor subtypes (Reubi et al., 2000
). After drying, slides were apposed to a 125I-sensitive Hyperfilm (Amersham, Milan-Italy) for 18 days; the film was then developed and autoradiograms were captured via a Panasonic Telecamera (Canon Objective Lens FD 50 mm, 1:3.5), and densitometric quantification was accomplished with a computer-assisted image analyzer system (VIDAS-Zeiss, Germany) running National Institutes of Health Image software. Values for binding (pmol/mg wet tissue weight; means ± SEM) were determined by comparison of two-dimensional images of a tissue section with variable quenching and consistency to a plastic standard of known radioactivity, as reported elsewhere (Facciolo et al., 2002b
).
sst3 In situ hybridization histochemistry.
For the next phase of the study, the brains of other animals were quickly removed from the skull, rapidly frozen using powdered dry ice for a very brief period, and then immediately used for in situ hybridization histochemistry assay, as suggested by other investigators (Siegel, 1998). Coronal frozen-fresh brain sections (at a thickness of 12 µm; two sections per slide) from PND 7 (n = 4) and adult (n = 4) rats were used for all treatment groups (BPA400; BPA40; OIL) and processed for in situ hybridization. Hybridization was performed on brain sections fixed for 5 min in 4% formaldehyde using oligonucleotide sst3 probes (Genosys, UK) of 40 bases in length according to previously described methods (Facciolo et al., 2002a
), with some modifications. The probes, which were the same as (sense) or complementary to (antisense) sst3 of mammalian mRNA sequences (Thoss et al., 1995
), were labeled to a specific activity of 2.5 x 108 cpm/µg on the 3' end with terminal deoxynucleotide transferase (Boehringer) and radiolabeled 35S-deoxyadenosine 5'(
-thio)triphosphate (NEN). Hybridization solution containing 4 x 105 cpm of either 35S-labeled oligonucleotide antisense or sense (control) probes to sst3 mRNA was used. After hybridization, the labeled tissue was extensively washed in different SSC buffers, dipped in distilled water, air-dried, and subsequently exposed to a 125I-sensitive Hyperfilm for a period of 15 days. Next, the developed films were analyzed in the same manner as for the autoradiography receptor study, applying a standard curve generated with 14C standards (Amersham), and values (pmol/mg wet tissue weight; means ± SEM) for BPA-treated groups were expressed as a percentage with respect to the OIL group. For histological verification of some hypothalamic and extrahypothalamic areas, the cytoarchitectonic study was performed on counterstained (cresyl violet stained with 0.5% acetate) sections, and brain areas were reported in the exact manner as they are identified in the Paxinos and Watson atlas (Paxionos and Watson, 1986
), except that the stratum radiatum hippocampal CA1 field and the lacunosum moleculare CA1 field of the hippocampus in the present work were indicated as a single area, the RAD.
BPA and sst3- GABAA subunit interaction.
To evaluate interaction of sst3 with GABAA receptor subunits, adjacent frozen-fresh brain sections (two sections per slide) of the same adult and PND 7 rats of the OIL group used for in situ hybridization histochemistry were incubated in a similar fashion as previously described. However, before proceeding with fixation procedure, brain sections were preincubated for 68 h in Tris HCl buffer, pH 7.4, in the presence of different concentrations (1 nM100 µM) of highly selective agonists of some
GABAA receptor subunits: the imidazopyridine zolpidem (
1; Synthelabo Recherche, Bagneux France), the benzodiazepine flunitrazepam (
2/3)/imidazobenzodiazepinone Ro 154513 (
4; Hoffmann-LaRoche, Basel), and the imidazobenzodiazepine RY 080 (
5; kindly provided by Dr. J. M. Cook, University of Wisconsin-Milwaukee). The effects of the higher dose of BPA on interaction of sst3 with
1 and
5 subunits were evaluated on adjacent frozen-fresh brain sections of the same adult and PND 7 rats used for in situ hybridization histochemistry, in the presence or absence of the different concentrations (5500 nM) of two of the above selective agonists (zolpidem or RY080) that induced selectively greater mRNA levels. The relative sst3 mRNA levels were expressed as a ratio (BPA ± zolpidem or RY 080 with respect to OIL ± selective agonists).
Statistical analysis.
For the competition study, binding values (pmol/mg wet tissue weight; means ± SEM) were based on a nonlinear least-squares regression analysis. In all cases, Ki values were calculated using the Cheng and Prusoff equation: Ki = IC50/[1 + ( C/Kd)], where C is the concentration of 125I-Tyr1-ss-14, and Kd is the dissociation constant of the radioligand. The effects of the two BPA doses on sst3 mRNA levels with respect to controls were evaluated using a one-way analysis of variance (ANOVA). If the ANOVA was significant, each treatment condition was evaluated by Dunnett's test ( = 0.05). The statistical significance of the role of the GABAA receptor
subunit agonists on sst3 mRNA levels of all treatment groups was evaluated using a one-way ANOVA, followed, when a significant p value was equal to or less than 0.05, by the Neuman-Keuls multiple range post-hoc test.
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RESULTS |
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DISCUSSION |
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From the comparison of the effects induced by the two BPA doses, it was possible to demonstrate, in a similar manner for the other major subtype-sst2 (Facciolo et al., 2002b), that the higher dose was responsible for evident heterogeneous sst3 mRNA levels. Indeed, such a dose accounted for early sst3 mRNA modifications in those hypothalamic and extrahypothalamic areas that are considered to be main targets of BPA-dependent differentiation events, at least in PND 7 rats. In particular, the greater sst3 transcript variations detected in hypothalamic areas such as Pe and Arc tend to emphasize the neuroendocrine importance of these major female estrogen-enriched hypothalamic targets (McEwen, 2002
), especially under the influence of the higher BPA dose. This is particularly significant for the very low sst3 mRNA levels observed in Pe of the developing rat, a condition that appears to be contrary to the high estrogen-dependent somatostatin production and, as a consequence reduced GH release levels that are typical of such a biological period (Simonian et al., 1998
). It would be interesting at this point to establish whether the early actions of BPA toward the acceleration of puberty (Howdeshell et al., 1999
) may be consistent with elevated GH secretion.
Interestingly, the greater BPA-dependent sst3 mRNA densities occurred in the presence of the selective GABAA receptor agonists zolpidem and RY 080. A relationship that not only corroborates the importance of this GABAA receptor subunit in BPA-dependent activities (Aoshima et al., 2001
) but also underlies the specificity of
1 and
5 isoforms toward the promotion of somatostatin functions through the inhibition of GABAergic interneurons (Bassant et al., 2005
). Even in this case, it was the early postnatal period that displayed greater GABAA-dependent BPA effects, which tend to further strengthen the importance of such a biological period during the onset of estrogen-dependent neural plasticity events.
It is exactly during this biological period that the formation of axo-somatic contacts and dendritic spines occur (Murphy and Segal, 1996; Wooley and McEwen, 1996
), as does early assembly of the GABAA receptor complex (Scotti and Reuter, 2001
). However, some hypothalamic areas did not respond to the early GABAA-dependent BPA effects, a condition that was notable for VMN, a major hypothalamic nucleus implicated in reproductive and feeding behaviors, in which no sst3 transcript variations occurred after exposure to zolpidem. This result suggests that, during the early postnatal age, VMN is probably not a preferential target of zolpidem-dependent BPA estrogen-like actions, a finding that coincides with the
1 subunit of the GABAA receptor not being fully assembled during the same period in the rat (Davies and McCarthy, 2000
).
It is worthwhile to note that sst3 mRNA variations were not only typical of the early biological stages, as demonstrated by changes resulting in some extrahypothalamic areas of adults. In fact, the greater post-pubertal sst3 mRNA levels appear to rely on the two subunits of the GABAA receptor, a relationship that tends to overlap the early BPA effects occurring predominantly outside the hypothalamus and that responds to elevated quantities of estrogen receptors being located in these and other extrahypothalamic areas after prolonged exposure to BPA (Aloisi et al., 2001
). Consequently, the high densities of both
and ß estrogen receptor subunits promoting estrogen-like BPA actions (Ramos et al., 2003
) appear to be determining factors responsible for the inhibition of higher cerebral activities such as learning, memory, and sensory functions (Negishi et al., 2003
), despite the evident modulatory actions of different neurotransmitters (Segarra et al., 1998
) that strongly depend on these estrogen subunits.
Taken together, these results provide direct evidence that BPA is capable of altering early neurobiological activities via the regulation of sst3 mRNA levels. The persistent exposure to the higher doses of this xenoestrogen during pregnancy and lactation appears to be related to the modifications of a variety of physiological and behavioral parameters (Dessì-Fulgheri et al., 2002; Negishi et al., 2004
), probably as a consequence of the regionally specific GABAA
1,5dependent variations of sst3 mRNA levels. However, the influence of BPA on the developing rat brain is probably not accomplished through modulation of estrogen responses alone, but may also require subtle developmental changes of other neuronal and endocrine systems. It is obvious that we are still at the beginning, but knowledge of BPA estrogen-like activities might bring us closer to an understanding of molecular cross-talking mechanisms of this somatostatin receptor subtype under both stressful and beneficial neural conditions such as pain and nociception (Aloisi et al., 2002
) or in the shaping and organization of dendritic formation during rat neonatal life, even after a 100-fold greater BPA concentration than that of estradiol (Shikimi et al., 2004
).
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ACKNOWLEDGMENTS |
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