ToxSci Advance Access originally published online on May 21, 2007
Toxicological Sciences 2007 98(2):582-588; doi:10.1093/toxsci/kfm115
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Relationship between Embryonic Histonic Hyperacetylation and Axial Skeletal Defects in Mouse Exposed to the Three HDAC Inhibitors Apicidin, MS-275, and Sodium Butyrate
Department of Biology, University of Milan, via Celoria, 26, 20133 Milan, Italy
1 To whom correspondence should be addressed. Fax: +39-02-50314802. E-mail: elena.menegola{at}unimi.it.
Received March 7, 2007; accepted May 3, 2007
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ABSTRACT |
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Some histone deacetylase inhibitors (HDACi) have recently been related to teratogenic effects in rodents. Skeletal defects have been directly associated with embryonic hyperacetylation of somitic nuclei after valproic acid or trichostatin A exposure in vivo. Albeit the antitumoral activity of HDACi has been classically related to chromatin condensation due to histonic lysine hyperacetylation, nonhistonic proteins have also been suggested as an HDACi target. The aim of this work was the study of the effects of three HDACi (apicidin, API; MS-275; sodium butyrate, BUT) on mouse development and their activity on embryonic histonic and nonhistonic proteins. Pregnant mice were ip treated with 10 mg/kg body weight API, 25 mg/kg MS-275, 2000 mg/kg BUT or with the vehicle alone on day 8 post coitum. Embryos were extracted 1, 2, or 3 h after treatment and Western blotting (using antibodies antihyperacetylated histone H4, antiacetylated lysine, or antitubulin) and immunohistochemistry (using the antibody antihyperacetylated histone H4) were performed. Fetuses, explanted at term of gestation, were double stained for bone and cartilage to detect skeletal abnormalities. The studied HDACi were teratogenic. The specific axial skeletal malformations were fusions or homeotic respecifications. These molecules induced hyperacetylation restricted to somitic histones. The hyperacetylation index of histone H4 as well as immunohistochemical and skeletal analyses indicated BUT as the less active molecule. These new data on effects of API, MS-275, and BUT on development suggest histonic hyperacetylation as the mechanism for the induction of the observed skeletal abnormalities.
Key Words: HDACi; teratogenesis; embryo; immunohistochemistry; Western blot; somite.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFundingREFERENCES |
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Histone deacetylase inhibitors (HDACi) are emerging as a new class of anticancer agents. Currently, several chemical classes of natural and synthetic HDACi have demonstrated to inhibit histone deacetylase enzyme and to induce histonic acetylation. Among them, nowadays, sodium phenyl-butyrate, SAHA, LAQ824, FK228, MS-275, CI-994, pyroxamide, and valproic acid (VPA) are in phase I or II clinical trials for cancer patients (Lin et al., 2006
). In spite of their different molecular structure, the active HDACi can be characterized by the common property of inhibiting deacetylation of the lysine residue of the histone tails due to a common pharmacophore consisting of a zinc-binding group, a linker domain, and a surface recognition domain (Jones et al., 2006).
As the acetylation status of histone lysine residues plays a crucial role in modulating chromatin structure and gene transcription, the antitumoral activity of HDACi has been classically related to chromatin condensation and consequently to an altered gene expression in tumor-inducing growth arrest, differentiation, apoptosis, and angiogenesis inhibition (Johnstone, 2002).
This mechanistic approach, however, does not consider that eukaryotic HDACs also acetylate nonhistonic proteins and nonprotein molecules such as polyamines or other substrates. So, although histones represent the most abundant HDAC substrate, alterations of components of the acetylome have to be considered as a potential HDACi-related mechanism. HDAC-related acetylation of nuclear factors, nuclear import proteins, and cytoplasmic factors has been strictly related to protein stability, protein-protein interaction, protein localization, and DNA binding of transcription factors (Minucci and Pelicci, 2006). Given these pleiotropic effects of HDACs on both histone and nonhistone substrates, the effects on the entire acetylome have to be taken into account in order to understand the properties of HDACi.
Recently, the HDACi VPA and trichostatin A (TSA) have been related to mouse embryonic histone hyperacetylation (Menegola et al., 2005; Nervi et al., 2001) and to dysmorphogenesis of the axial skeleton (Menegola et al., 2005). In particular, hyperacetylation of histone H4 was detected both in total embryonic homogenates and immunohistochemically at the level of the embryonic organs giving rise to the vertebral column (somites) after a single treatment of mice with 400 mg/kg VPA or 16 mg/kg TSA at day 8 post coitum. The observed fetal abnormalities were fusions of vertebrae and ribs, duplication of segments, and homeotic respecification (i.e., transformation of body parts into the likeness of something else as defined by Bateson, 1894). The homeotic respecification induces a general shift of segment morphology with posterior or anterior transformation of the next more caudal segments. Similar teratogenic effects have also been described after treating mice, zebrafish, and Xenopus laevis with VPA and after zebrafish and X. laevis treatment with TSA. Developmental defects were also obtained in invertebrate (Drosophila, starfish, and sea urchin) embryos after TSA exposure and in vertebrate or invertebrate HDAC mutant or knockout embryos (for a deep review see Menegola et al., 2007).
The objectives of this investigation were to extend the knowledge of HDACi effects on embryo development and to discriminate the HDACi targets (histone or nonhistone proteins) on mouse embryonic tissues. For these purposes, we selected three HDACi from different chemical classes: apicidin (API), MS-275, and butyric acid (sodium butyrate, BUT).
API, a cyclic tetrapeptide, is a fungal metabolite isolated from Fusarium pallidoroseum with a potent broad spectrum of antiprotozoal activity against apicomplexan parasites (Darkin-Rattray et al., 1996) and antiproliferative activity blocking cell cycle and inducing apoptosis in various cancer cell lines (Han et al., 2000; Ueda et al., 2007).
MS-275 is a synthetic benzamide derivative with a broad spectrum of activity against hematopoietic and nonhematopoietic malignant cells inhibiting cell growth by differentiation and apoptosis induction (Jaboin et al., 2002; Ryan et al., 2005; Saito et al., 1999).
BUT is a short-chain fatty acid produced in the colon lumen as a consequence of microbial degradation of dietary fibers. It is a known HDACi, inducing growth inhibition, primarily by cell cycle arrest, differentiation, and/or apoptosis, in many tumor cell types (Chen et al., 2003; Davie, 2003; Kouraklis and Theokaris, 2002; Kennedy et al., 2002).
Pregnant mice were dosed with the three selected molecules and processed using a protocol similar to that previously used for VPA and TSA in order to detect embryonic histone H4 hyperacetylation and skeletal abnormalities. Embryonic homogenates were finally used to verify the acetylation status of the entire proteome in order to detect and characterize embryonic nonhistone proteins altered by the selected HDACi exposure.
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MATERIALS AND METHODS |
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Animals
Female CD1 mice (20–25 g body weight) were purchased from Charles River Laboratories (Calco, Italy) and acclimated for 1 week prior to the initiation of experiment. Animals were housed in standard conditions (light cycle 12 h, light from 7 A.M. to 19 P.M.; humidity 55 ± 5%, T = 22 ± 2°C). The animals had free access to food (4RF21, Charles River Laboratories) and water. Virgin females were caged overnight with CD1 males of proven fertility; the presence of a vaginal plug the following morning (day 0 of gestation, E0) was considered as evidence of mating.
Experimental Design
Animals were randomly assigned to a treatment group at E0.
E8 pregnant mice (embryonic stage 5–15 somites) were ip treated with 0.2 ml/10 g body weight of appropriate solutions to dose 10 mg/kg body weight API (Sigma, Milan, Italy, dissolved in [dimethyl sulfoxide] DMSO:saline solution 1:4), 25 mg/kg body weight MS-275 (Sigma, dissolved in DMSO:saline solution 1:4), 2000 mg/kg body weight BUT (Sigma, dissolved in saline solution). A control group was dosed with 0.2 ml/10 g body weight of DMSO:saline solution at the same time. The dosing regimen was selected for each molecule on the basis of previous range-finding tests. Five mice/group for Western blotting and immunohistochemical analysis were sacrificed by CO2 asphyxia 1, 2, 3 h after the treatment, and 10 mice/group were sacrificed at term of pregnancy (E18) for skeletal examination.
Statistics
Data given as mean ± SD were calculated using the litter as the unit of comparison and analyzed for statistical significance by ANOVA followed by Tukey's test. For malformation analysis, fetuses were the experimental unit, and the percentage of malformed fetuses was analyzed using the chi-square test. The level of significance was set at p < 0.05.
Analysis at Term of Gestation
At necroscopy, the following parameters were assessed: number of live fetuses, dead fetuses and resorptions. The postimplantation loss index ([dead fetuses + resorptions]/[total implantation sites] x 100) was calculated. Live fetuses explanted from the uteri were externally examined, weighed, and all processed for double staining of bone and cartilage using Alizarin Red S (Fluka, Milan, Italy) and Alcyan Blue GX (Sigma), respectively, according to the method previously described (Menegola et al., 2001). Placental weights were recorded.
Analysis at Midgestation
Embryos explanted from each female were randomly assigned to Western blot analysis or immunohistochemistry.
Western blotting.
Total cellular extracts were prepared from embryos explanted in saline solution. Samples were sonicated and centrifugated at 16,500 x g for 10 min at 4°C. Protein concentration was measured by the Bradford method (1976). The supernatants were added to XT sample buffer (Bio Rad, Segrate, Milan, Italy) and heated at 100°C for 5 min for protein denaturation.
Equal amounts of protein (22.5 µg) were resolved by 10–20% sodium dodecyl sulfate polyacrylamide gel (Bio Rad) under reducing conditions and transferred to nitrocellulose membrane. Immunoblotting was performed using polyclonal antibody to histone H4 hyperacetylated (Upstate, Segrate, Milan, Italy) (dilution 1: 8000) to acetylated lysine (Cell Signaling Technology, Celbio S.p.A., Pero, Milan, Italy) (dilution 1:1000) or to tubulin (Sigma) (dilution 1:200) to check protein loading. After incubation with secondary antibodies conjugated to alkaline phosphatase (anti-rabbit, 1: 2500 dilution; anti-mouse 1:2500 dilution) (Sigma), protein expression was colorimetrically detected with BCIP/NBT (5-bromo-4-chloro-3-indolyl-phosphate and nitroblue tetrazolium) (Sigma). Quantitative analysis of signals was performed using the program Quantity One (Bio Rad). The integrated signal intensity obtained after immunodetection of hyperacetylated histone H4 was normalized on that obtained after immunodetection of tubulin and the means, obtained using data recorded in the different experiments, statistically analyzed using ANOVA followed by Tukey's test.
Immunohistochemistry.
After fixation with 3% paraformaldehyde 6 h at 4°C, some embryos (five from each group), collected 2 h after treatment, were embedded in paraffin and sectioned (5 µm). Immunolocalization was performed using the anti-hyperacetylated histone H4 antibody used for immunoblotting (overnight, diluted 1: 8000). After incubation with secondary antibody anti-rabbit IgG peroxidase (Boehringer) (dilution 1: 40) the staining was carried out with the substrate solution, diaminobenzidine (Sigma) and H2O2.
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RESULTS |
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Data Recorded at Term of Gestation
Exposure of mice to the selected dosages of API, MS-275, and BUT did not produce any sign of maternal toxicity as shown by body weight gain during gestation, food and water consumption, and by the observation of clinical signs (data not shown).
The means of implantation, dead, resorbed conceptuses, the postimplantation loss index, and the means of fetal and placental weights were not different in treated groups in comparison to control (data not shown).
By contrast, all the tested molecules were teratogenic as observed after skeletal examination (Table 1). The percentage of abnormal fetuses was similar for API, MS-275, and BUT (nearly 80%). The observed abnormalities were typical and included fusions of vertebrae, ribs, and sternebrae; cervical rib; extra sternebra; and shifts of typical morphological characters from axial elements to adjacent segments (Table 1; Fig. 1 and Fig. 2). As far as malformations described as fusions are concerned, no fetuses were affected in the control group, and a different percentage of affected samples was recorded in the treated groups, with a marginal percentage of fetuses with fusions in BUT group and a statistically comparable percentage of affected fetuses in API and MS-275 groups (Fig. 2b), significant versus control group. On the other hand, the abnormalities that can be considered as homeotic respecification of segments (cervical rib, vertebrae, or rib morphological shifts) were present in similar percentages in all treated groups, and, with a minor incidence, in the controls too (Fig. 2c).
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Data Recorded at Midgestation
Western blotting.
Western blotting, performed on homogenates obtained from API, MS-275, and BUT-exposed embryos explanted 1, 2, and 3 h after treatment, showed clear hyperacetylation of hystone H4 in comparison to control, which, on the contrary, only showed an extremely weak signal. The quantification of the intensity of the hyperacetylated H4 expression, normalized on tubulin levels, showed all the tested molecules active in inducing hyperacetylation and indicated API and MS-275 as the most active molecules (Fig. 3 and Fig. 4). In addition, API and MS-275 maintained high hyperacetylation level till 2 and 3 h from treatment, respectively, while in the BUT homogenates, the ratio of the signals dramatically decreased from 2 h onward (Fig. 4). In order to perform Western blotting to verify the acetylation status of the entire proteome, using the antibody antiacetylated lysine, the times with peak hyperacetylation index (API 2 h, MS-275 3 h, BUT 1 h groups) were selected. In all groups the only proteins with acetylated lysine were histones (H2, H3, H4). As far as H4 is concerned, the signal was perfectly comparable to that detected after the use of antihyperacetylated H4 antibody (Fig. 5).
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Immunohistochemistry.
Immunohistochemical analysis was restricted to control groups with peak hyperacetylation index (and API 2 h, MS-275 3 h, BUT 1 h after treatment), in order to localize histone H4 hyperacetylation in histological sections. No control embryos showed positive reactions in all examined tissues (Fig. 6a). By contrast, a specific signal was detected at the level of somites after immunostaining of API, MS-275, and BUT (Fig. 6b–d). Immunoreaction was clearly more evident for API and MS-275 samples.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFundingREFERENCES |
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In spite of the absence of maternal toxicity and general embryotoxicity, API, MS-275, and BUT proved to be teratogenic after ip injection of pregnant female mice on day 8 post coitum. The detected abnormalities were extremely specific, restricted to the axial skeleton, and completely comparable with those described after rodent embryo exposure to HDACi belonging to other chemical classes (VPA and TSA) (Menegola et al., 2005
) as well as to boric acid, which has been recently added to the list of molecules exerting HDACi activity (Di Renzo et al., 2007). The severe abnormalities consisted of fusion of vertebrae, ribs, or sternebrae, changes in the typical number of segments for each axial region, and other morphological changes ascribable to homeotic respecifications. Fusion of ribs or vertebrae is severe permanent malformations due to the incapacity of somites to separate from each other. The genesis of fused sternebrae has, on the other hand, a different basis: sternebrae are initially constituted by two paired symmetric ossification points, induced to form by the position of the ribs reaching the sternum. Subsequently, the paired structures fuse together forming a median structure. An incorrect or asymmetric insertion of ribs generates asymmetric ossification points that, afterward, fuse with the anterior or posterior sternebra instead of fusing with the paired ossification point. As a consequence, the origin of sternal malformation is secondarily related to the abnormal rib morphogenesis. Finally, homeotic respecifications have been correlated to genetic defects produced by abnormal expression of genes named homeotic genes, cloned initially in Drosophila (Akam et al., 1988; Gehring and Hiromi, 1986) and then also identified in vertebrates (Hox genes) (McGinnis et al., 1984; for an exhaustive review on murine Hox genes see Deschamps and van Nes, 2005). Homeotic transformation also occurs after xenobiotic exposure during embryogenesis. The most known molecule related to Hox code alteration is retinoic acid (Kessel, 1992; Kessel and Gruss, 1991), but a number of other molecules, including VPA, exert, directly or indirectly, similar effects (Faiella et al., 2000; Kawanishi et al., 2003). Similarly to other molecules inducing homeotic transformations, as widely described in literature, API, BUT, and MS-275 were able to induce a cascade of events resulting in morphological changes both of segments in formation at the time of treatment and of more caudal elements. Albeit a direct correlation between hyperacetylation and teratogenicity is not still demonstrated, there is at least good circumstantial evidence suggesting that hyperacetylation is the mechanism involved in HDACi-related teratogenic effects.
The capability of API, MS-275, and BUT to induce a high percentage of malformed fetuses (more than 50%), in the absence of embryolethal effects, has been considered the essential requirement for the analysis of embryos at midgestation (when abnormalities are not detectable). After fetal analysis, these three compounds induced a similar percentage of malformed fetuses (nearly 80%), although only API and MS-275 were able to induce high percentages of fusions at term of gestation.
On the other hand, all the applied techniques performed at midgestation (Western blotting and immunohistochemistry) revealed a different potency of the three molecules, and BUT proved to be the least active in inducing hyperacetylation. The different kinetic of embryonic effects of BUT could be the reason of such a result; the hyperacetylation level decreased rapidly for BUT (its normalized value had been nearly halved after 2 h), but increased 2 h after API treatment, and for the entire period of analysis for MS-275.
The axial skeleton originates from somites in all vertebrates. Somites are transient embryonic structures giving rise to dermal, muscular, and skeletal structures of the trunk. The relevant findings of the present work are the description of developmental effects of API, MS-275, and BUT (never investigated before) resulting in axial malformation and the specific histone hyperacetylation at the level of embryonic axial organs (somites) in embryos explanted a few hours after maternal treatment. Western blot analysis using the antiacetylated lysine antibody showed that the selected HDACi are specifically active at the level of nuclei and that the molecular targets are histones. This evidence improves our knowledge of the activity of HDACi on embryonic developing tissues, as only the activity of H4 histone had been previously investigated.
This work reports two completely new and relevant findings: (1) H2, H3, and H4 represent the chromatin part susceptible to HDACi activity and (2) in embryos the rest of the acetylome is not modified by the molecules under study (as demonstrated by using antibodies antiacetylated lysine) and confirms that the targets of HDACi in embryos are the histone core proteins of somites. The reason for this marked specificity is so far unknown.
In conclusion, overall analysis of the data indicates that API, MS-275, and BUT are teratogenic in mice, inducing specific and severe axial skeletal malformations. The malformations are similar to those observed after mouse exposure to other HDACi, suggesting a common mechanism of action for all the studied HDACi. Even if the pathogenic pathway has not been identified yet, the probable mechanism could be the specific hyperacetylation of histones in specific embryonic target organs (somites). No effects were recorded at the level of other embryonic tissues and at the level of other proteins. As the literature is lacking in data on the effects of API, MS-275, and BUT on embryo development, on HDACi activity on embryonic cells, and on the effects of the three selected molecules on acetylome, the present work makes a new contribution to both the classical and the mechanistic teratogenic approaches.
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Funding |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONFundingREFERENCES |
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This work was supported by found FIRST from the University of Milan, Italy.
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ACKNOWLEDGMENTS |
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The Authors would like to acknowledge Mr. Calogero Bella for his skillful technical assistance.
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