* Department of Pedodontics and Orthodontics, Institute of Dentistry, University of Helsinki, Helsinki, Finland;
Department of Oral Pathology, Institute of Dentistry, University of Helsinki, Helsinki, Finland;
Department of Environmental Health, National Public Health Institute, Kuopio, Finland; and
Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Helsinki, Finland; and
¶ Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
Received April 26, 2002; accepted July 11, 2002
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ABSTRACT |
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Key Words: dioxins; 2,3,7,8-tetrachlorodibenzo-p-dioxin; rat incisor; dentin; enamel; odontoblasts; enamel organ; dental defect; dose response; aryl hydrocarbon receptor.
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INTRODUCTION |
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The acute lethality of the most toxic dioxin congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), varies markedly not only among animal species, but also among strains of a given species (Pohjanvirta and Tuomisto, 1994). For example, the difference in LD50 is 1000-fold between the resistant Han/Wistar (H/W) and the sensitive Long-Evans (L-E) rats (Pohjanvirta et al., 1993
; Unkila et al., 1994
). In general, resistance of a rat strain to the acute lethality of TCDD fails to predict responsiveness to other toxic and developmental effects.
The majority of TCDD effects, including developmental effects such as cleft palate and hyperplasia of the ureteric epithelium, leading to hydronephrosis in embryonic mice, are thought to be mediated by the aryl hydrocarbon receptor (AhR) (Abbot et al., 1994; Bryant et al., 1997; Mimura et al., 1997
; Peters et al., 1999
; Pohjanvirta and Tuomisto, 1994
). AhR is a ligand-activated intracellular transcription factor, the definite physiological function of which is unknown. Dimerization of the activated AhR with the AhR nuclear translocator (ARNT) protein and binding of the heterodimer to dioxin-responsive elements of DNA eventually leads to the transcription of xenobiotic-metabolizing enzymes (Schmidt and Bradfield, 1996
). However, there are also data suggestive of alternative signaling pathways (Blankenship and Matsumura, 1997
; Peters et al., 1999
), such as the c-src tyrosine kinase pathway (Enan et al., 1998
), possibly cross-coupled with epidermal growth factor receptor (EGFR) signaling. Dependence of depolarization and the consequent functional failure of the newly differentiated dental cells on the expression of EGFR, as shown in cultured mouse embryonic molars, implies the involvement of EGFR signaling in early dental toxicity of TCDD (Partanen et al., 1998
).
The molecular basis for the exceptional resistance of H/W rats to the acute lethality of TCDD lies primarily in a mutated allele of AhR (Ahrhw) (Pohjanvirta et al., 1998; Tuomisto et al., 1999
) and an allele Bhw of a thus far unidentified gene. Besides conferring resistance to the acute lethality, the mutation involving the transactivation domain of AhR and leading to an altered reading frame and the consequent shortening of the protein product also accounts for the resistance of H/W rats to hepatotoxicity (Tuomisto et al., 1999
), liver tumor promotion activity (Viluksela et al., 2000
), and bone effects (Jämsä et al., 2001
) of TCDD, but does not account for the cytochrome P450 (CYP) 1A induction or thymic atrophy. Based on these end point-dependent sensitivity differences, we have classified the AhR-mediated effects of TCDD into two categories (Simanainen et al., 2002
; Tuomisto et al., 1999
). Effects that are similar in both strains, and hence independent of the genotypic variation of AhR (e.g., CYP1A activity), are called type I effects. Type II effects (e.g., acute lethality), on the other hand, show suppressed efficacy (and potency) in H/W rats or other rats with Ahrhw genotype.
Teeth develop as a result of inductive interactions between cells of the ectodermal lining of the first branchial arch and the subjacent mesenchyme. Development proceeds via consecutive morphogenetic stages to the differentiation of tooth-specific cells and the subsequent formation and mineralization of dental matrices (Thesleff and Nieminen, 1998). In contrast to the molars, rat and mouse incisors erupt continuously. In response to the physiological attrition at the incisal, erupted part of the tooth, new tooth substance is constantly generated at the basal, germinative end (Shellis and Berkovitz, 1981
). Depending on the dose, experimental design, and stage of tooth development, TCDD interferes with molar tooth germination and/or morphogenesis, with consequences varying from total failure of tooth development and arrested root formation to reduced tooth size (Kattainen et al., 2001
; Lukinmaa et al., 2001
). Sensitivity of early rat molars to TCDD toxicity seems to increase to some extent with the genetically determined sensitivity of the rat strain to the acute lethality of TCDD. To define the dose response and histological characteristics of incisor toxicity after long-term exposure to TCDD, and to see whether the impairment of the incisor tooth formation by TCDD is associated with the resistance of the rat strains to its acute lethality, we studied responses in resistant H/W and sensitive L-E rats.
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MATERIALS AND METHODS |
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Animals and animal care.
A total of 45 rats, 25 outbred female Han/Wistar (Kuopio; H/W) and 20 inbred female Long-Evans (Turku/AB; L-E) rats, were included. The animals were obtained from the breeding colony of the National Public Health Institute (Kuopio, Finland), which is kept in a specific pathogen-free barrier unit. Regular health surveys suggested by the Federation of European Laboratory Animal Science Associations (FELASA; Rehbinder et al., 1996) indicate that these rats are free from typical rodent pathogens. We housed the rats in stainless steel wire-bottomed cages, five rats per cage, and provided standard pelleted R36 feed (Ewos, Södertälje, Sweden) and tap water ad libitum. The room was artificially illuminated from 7:00 to 19:00 h. The ambient temperature was 21.5 ± 1°C, and the relative humidity was 55 ± 10%.
Experimental design.
Experimental groups and dosages are shown in Table 1. The animals used in this study were a part of an extensive liver tumor promotion study. This paper reports the effects of TCDD on the incisor teeth of nonhepatectomized/noninitiated rats. Effects on liver tumor promotion (Viluksela et al., 2000
) and skeleton (Jämsä et al., 2001
) have been reported previously. In our earlier study on H/W rat incisors, 1000 but not 50 µg/kg TCDD given to a lactating dam clearly impaired dentinogenesis of the pup incisors (Lukinmaa et al., 2001
). The dosage used here was thus expected to render the dose response comparison between the two strains possible. At the beginning of dosing, the rats were 10 weeks old and they weighed (mean ± SD) 184 ± 14 g (H/W) and 164 ± 12 g (L-E). TCDD was administered to the rats by sc. injections (2 ml/kg) once a week for 20 weeks. To rapidly achieve the kinetic steady state, the first dose was a loading dose five times as large as the 19 consecutive maintenance doses (Flodström and Ahlborg, 1989
). Incisors of a 10-week-old rat are fully mature. As the incisor tooth material is replaced about every 62 days (Shellis and Berkovitz, 1981
), 20 weeks of exposure covered two life cycles of the tooth and made it possible to study the effects of TCDD from stem cell proliferation and differentiation to the completion of matrix formation. The control group rats were similarly treated with corn oil. The rats were observed daily and weighed weekly. They were anesthetized with CO2/O2 (70%/30%) and terminated by cutting the aorta.
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Tissue specimens and macroscopic/stereomicroscopic examination of the incisors.
The mandibles were dissected, deprived of extraneous soft tissues, and fixed with and kept in 10% neutral-buffered formalin until use. The mandibles were sagittally bisected, and the lower incisors were inspected macroscopically and stereomicroscopically to estimate tooth color and the status of the dental pulp in the erupted part of the teeth. The physiological lingual attrition surface was gently examined with a dental probe.
Preparation of the tissue specimens for histological examination.
The left halves of the mandibles were demineralized with ethylenediaminetetra-acetic acid (EDTA; 0.33 mol/l) at about 22°C under mild shaking for 3 months. To minimize the drawbacks of oblique sectioning of the steeply curved incisors, three blocks were transversely cut from the demineralized mandible halves, making use of a stereomicroscope and anatomic landmarks of the teeth and periodontal tissues. Starting from the incisal tooth tip, the first block extended midway along the lingual attrition surface of the dentin. The second block extended from the basal margin of the attrition surface to the level of the mesial alveolar bone margin, and the third block extended basally from the lingual bone margin to the vicinity of the labial bone margin (Fig. 1). The blocks comprising teeth and periodontal tissues were conventionally embedded in paraffin, each in a cassette of its own. Representative series of transverse sections were serially cut at 5 µm, proceeding in the incisal to basal direction, and stained with hematoxylin and eosin.
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RESULTS |
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As in the unaffected teeth (Fig. 4A), the ameloblasts at level III ranged in shape from high or low columnar to squamous. One of five H/W rats and two of five L-E rats showed squamous metaplasia and pronounced proliferation of the postsecretory enamel organ with scattered apoptotic cells. In the H/W rat and in one of the two L-E rats exhibiting squamous metaplasia and marked proliferation in the enamel organ, but in none of the controls or at lower doses, Rushtons hyaline bodies were visible in the squamous epithelial islands (Fig. 4B
).
Appearance of H/W rat lower incisors at 170 µg/kg TCDD.
Midway along the attrition surface (level I), the pathologically large pulp chamber was wide open to the dentin surface and as at the corresponding levels of the unaffected teeth, the pulp tissue lacked structural elements (Fig. 5A). The nonmineralized predentin was abnormally thick. Above the mesial bone margin (level II), the pulp chamber, frequently encompassed by accentuatedly lamellar dentin, was extensive. Many pulpal blood vessels were calcified. The mineralization front in the predentin-dentin border was irregular (Fig. 5B
). Squamous metaplasia and accentuated proliferation of the enamel organ with apoptotic cells were evident in four of five rats, and one of the four exhibited intraepithelial Rushton bodies at level III.
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DISCUSSION |
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The lower incisors of young H/W rats given a single dose of 1000 µg/kg TCDD, apart from showing arrest of dentinogenesis, are smaller than normal and aberrant in shape (Alaluusua et al., 1993). Whether these changes result from interference with morphogenesis or are secondary to impaired matrix formation is unknown. Nonetheless, proliferation and differentiation of the dental cells remain continual. Even the highest cumulative dose of TCDD (170 µg/kg) used here did not alter the size or shape of the H/W rat incisors. However, consistent with the more basal (earlier) damage to the incisors at the TCDD dose of 170 than at 17 µg/kg, the teeth were more pronouncedly mottled and the pulp chamber was larger at the higher dose than the lower. We have previously shown that in utero/lactational TCDD exposure of rats to a single maternal dose as low as 1 µg/kg can arrest early third-molar tooth development. Rats with the Ahrhw allele were slightly but clearly more resistant than the sensitive rats (Kattainen et al., 2001
). Besides causing complete failure of rat and mouse molar tooth development, TCDD can damage newly differentiated ameloblasts and odontoblasts, reduce tooth size and arrest root formation (Kattainen et al., 2001
; Lukinmaa et al., 2001
; Partanen et al., 1998
). The TCDD responsiveness of rodent molars thus seems to extend from the earliest stages of tooth development, governed by epithelial-mesenchymal interactions, to deposition and mineralization of the dental matrices. Taken together, among major determinants of the morphological consequences of developmental dental toxicity of TCDD are not only the dose and stage of tooth development, but also the tooth type, i.e., whether the tooth is continuously erupting or not.
TCDD shares certain effects with epidermal growth factor (EGF). Accordingly TCDD, like EGF, accelerates the emergence of incisors of newborn mice into the oral cavity (Madhukar et al., 1984, 1988
). In addition, EGF receptor (EGFR) may be involved in the mediation of TCDD toxicity in cultured mouse embryonic molars (Partanen et al., 1998
). EGFR is transiently expressed in rat incisor preameloblasts and preodontoblasts (Davideau et al., 1995
). However, its reappearance only in maturation-stage ameloblasts seems to exclude EGFR signaling of TCDD toxicity in rat incisor odontoblasts once they have become secretory. The life cycle of the dental cells is fairly stable, and therefore a possible increase in the incisor eruption rate does not make them differentiate or lay down dental matrices any faster. The acceleration of eruption would leave odontoblasts and ameloblasts insufficient time to complete their functions, i.e., to deposit dentin to obliterate the pulp chamber before it is reached by the attrition, and to accumulate iron, respectively. Secretion of iron-containing compounds by predegeneration ameloblasts on the maturing enamel normally gives the labial surface of the erupted part of the incisor its characteristic brown-yellow color. However, an increased eruption rate, at least alone, would poorly explain the precocious death of odontoblasts and phenotypic alterations in the enamel organ visible histologically.
Disregarding the basic mechanism(s) of TCDD toxicity to rodent incisors, premature squamous metaplasia in the richly vascularized postsecretory enamel organ may have impaired the blood supply of ameloblasts, which normally facilitate iron metabolism, thus accounting for the color defect of the enamel. In addition, damage to not only odontoblasts, but also pulpal fibroblasts, may imply involvement of vascular failure. Although circulatory impairment caused by TCDD exposure is only beginning to be investigated in mammals, it is a well-recognized adverse effect of TCDD during early life-stage development in several fish species (Henry et al., 1997; Hornung et al., 1999
; Spitsbergen et al., 1991
; Teraoka et al., 2002
). It is characterized by a reduction of regional blood flow to various vascular beds that is probably secondary to reduced cardiac output. Significantly, there are also alterations in blood flow to the lower jaw associated with reductions in lower jaw length (Henry et al., 1997
; Hornung et al., 1999
; Teraoka et al., 2002
). Embryotoxicity caused by TCDD-induced vascular damage may involve apoptosis (Cantrell et al., 1998
).
The same rats used in this study were also studied for the effects on bone (Jämsä et al., 2001). Exposure to TCDD was shown to decrease bone mechanical strength as well as alter the geometry and mineral density. L-E rats were clearly more sensitive than H/W rats. Therefore, bone effects represent type II dioxin effects. Consistent with a type I effect independent of the genotypic variation of AhR, adult H/W and L-E rats seem to be similar in their sensitivities to TCDD-induced incisor toxicity. Furthermore, the bone effects were observed already at an order of magnitude lower dose (1.7 µg/kg) in L-E rats. Thus, bone and dentin, both representing mineralized tissues of mesenchymal origin, differ in terms of the association of their sensitivities with the expression of the mutated AhR.
To conclude, TCDD seems to cause two types of developmental dental defects in rats. First, the morphogenesis of molars is affected. This sequence of events involving epithelial-mesenchymal interactions is sensitive to low doses of TCDD and responds immediately by an arrest of early tooth (crown) development; later, TCDD at high doses interferes with root morphogenesis, leading to the formation of shorter than normal roots. The toxicological significance of these effects is emphasized by the fact that rat molars are developmentally similar to human teeth in that once they have developed, tooth material is not physiologically replaced. Second, matrix formation of the continuously erupting rat incisors is impaired at high doses of TCDD because of defective function of secretory/postsecretory cells. The major targets in incisors are the ectomesenchymal odontoblasts and, to a lesser extent, the epithelial enamel organ. The affliction of rat incisors at the stage of matrix formation is no longer dependent on epithelial-mesenchymal interactions, which govern both (molar) crown and root morphogenesis. The absence of definite sensitivity differences in the incisors between H/W and L-E rats, extensively differing in their resistance to the acute lethality of TCDD, implies that the effects of TCDD on the incisor teeth are not modified by the mutation in the transactivation domain of AhR.
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ACKNOWLEDGMENTS |
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NOTES |
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