* Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Food Toxicology, School of Veterinary Medicine, Hannover, D-30173 Hannover, Germany; and
National Public Health Institute, Department of Environmental Health, Kuopio, Finland
1 To whom correspondence should be addressed at Helen Håkansson, Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, SE-17177 Stockholm, Sweden. Fax: + 46 8 34 38 49. E-mail: helen.hakansson{at}imm.ki.se.
Received October 29, 2004; accepted March 29, 2005
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ABSTRACT |
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Key Words: TCDD; dioxin; retinoid; retinoic acid; retinol.
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INTRODUCTION |
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Since that initial investigation in Long-Evans and Han/Wistar rats, we have shown that TCDD alters all-trans-RA and retinoic acid metabolite concentrations in the liver, serum, and kidney of Sprague-Dawley rats following single doses of TCDD (Hoegberg et al., 2003; Nilsson et al., 2000
; Schmidt et al., 2003b
). However, to date, no study has investigated altered retinoid homeostasis at the levels of retinoic acid or retinoic acid metabolites following long-term low-dose TCDD exposure. Since, to date, over 500 genes have been shown to be retinoid regulated (Balmer and Blomhoff, 2002
), altered retinoid homeostasis at the level of retinoic acid or other signaling retinoid metabolites could have diverse effects on gene transcription and cellular function, which may vary dependent upon developmental stage. Consistent with this hypothesis, at the molecular level, Lorick et al. (1998)
showed that TCDD decreased the binding of all-trans-RA to retinoic acid receptors in cultured human keratinocytes. Several investigators have also demonstrated that TCDD exposure results in a loss of tissue responsiveness to all-trans-RA induced effects on tissue transglutaminase activity and expression, as well as other all-trans-RA induced genes including RARß and CRABP II in vitro (Krig et al., 2002
; Krig and Rice, 2000
; Rubin and Rice, 1988
; Weston et al., 1995
). On the other hand, our recent studies showed that acute oral TCDD exposure increased liver, serum, and kidney concentrations of all-trans-RA (Hoegberg et al., 2003
; Schmidt et al., 2003b
), which would seemingly support a case for hypervitaminosis rather than vitamin A deficiency. In accordance, it has more recently been appreciated that some of the signs of TCDD toxicity such as effects on bone and cleft palate may also resemble a case of vitamin A excess (Nilsson and Hakansson, 2002
). Thus TCDD may elicit a complex spectrum of effects on retinoid metabolism and retinoid-mediated gene transcription. These changes could then elicit signs of toxicity characteristic of vitamin A deficiency or hypervitaminosis dependent upon tissue type.
TCDD has repeatedly been shown to decrease serum total thyroxine and FT4 concentrations in rats following both single dose and repeated dose exposures (Bastomsky, 1977; Brouwer et al., 1998
; Pohjanvirta et al., 1989
; Potter et al., 1983
, 1986
; Sewall et al., 1995
; Van Birgelen et al., 1995
), but has not been assessed in Long-Evans and Han/Wistar rats following long-term exposure. Increased elimination of thyroxine following TCDD exposure has been suggested to occur as a result of induced activity of uridine diphosphoglucuronosyl transferase activity in the liver, leading to the formation of glucuronide conjugates, and decreased circulating levels of T4 (reviewed in Brouwer et al., 1998
). The extent to which alterations in thyroid hormone status portrays altered thyroid hormone function following TCDD exposure is not known, but thyroid hormones have been shown to modulate TCDD toxicity. For instance, coadministration of both retinoids and thyroid hormone increases the incidence of cleft palate formation in TCDD-treated mice (Abbott and Birnbaum, 1989
; Lamb et al., 1986
). In addition, retinoids and thyroid hormones and/or thyroidectomy have been shown to partially ameliorate effects of TCDD and other halogenated hydrocarbons on body weight loss and protract time to lethality in rats and mice following high dose exposure (Darjono et al., 1983
; Hakansson et al., 1991b
; Innami et al., 1974
; Neal et al., 1979
; Rozman et al., 1984
, 1985
), whereas retinoids also offered protection against thymic atrophy (Aust, 1984
). Although the effects of TCDD on retinoid and thyroid homeostasis are relatively well characterized in rats, little is known about the effects of TCDD on the vitamin D signalling system. However, recently Lilienthal et al. (2000)
showed that both 25-OH-D3 and 1,25-(OH)2-D3 were decreased in the serum of Long-Evans dams and offspring following exposure to a mixture containing dioxin-like polychlorinated biphenyls (PCBs). Though the mechanisms remain unknown, alteration of vitamin D homeostasis by dioxin-like compounds could have important effects on vitamin D target tissues such as bone, kidney and intestine, hematopoietic tissues, and skin.
Therefore, the major objective of the study was to establish whether long-term low-dose TCDD exposure altered retinoid homeostasis at the level of retinoic acid and retinoic acid metabolites in rats. Female Long-Evans and Han/Wistar rats were treated according to a tumor promotion protocol as described previously (Viluksela et al., 2000). Apolar retinoid analyses showed that partial hepatectomy and NDEA pretreatment did not result in notable differences in hepatic retinoid levels or TCDD concentration in the liver compared to nonhepatectomized/uninitiated animals. Subsequently retinoic acid and retinoic acid metabolite concentrations were determined in the liver, kidney, and plasma of partially hepatectomized/initated animals, 20 weeks after dosing with TCDD at calculated daily doses of 0, 1, 10, 100 and 1000 ng/kg bw/day. Additionally, 25-OH-D3 and FT4 were measured by radioimmunoassay in the plasma.
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MATERIALS AND METHODS |
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Animals.
Inbred female Long-Evans (Turku/AB) and outbred female Han/Wistar (Kuopio) rats were obtained from the breeding colony of the National Public Health Institute (Kuopio, Finland) and kept in an SPF barrier unit. Regular health surveys consisting of serological and bacteriological screening as suggested by Rehbinder et al. (1996) indicated that the animals were free of typical rodent pathogens. The rats were housed in stainless steel wire bottom cages, five rats per cage, and given standard pelleted R36 feed (Ewos, Södertälje, Sweden), and tap water ad libitum. The room was artificially illuminated from 7 A.M. to 7 P.M., and the ambient temperature was 21.5 ± 1°C and relative humidity 55 ± 10%.
Experimental Design.
The study design, optimised for investigating tumor promotion, is summarized in Table 1, and has been described in detail previously (Viluksela et al., 2000). Briefly, 5-week-old rats (ten animals/dose) weighing 70.1 ± 7.8 g (Long-Evans) or 81.7 ± 3.9 g (Han/Wistar) were partially (2/3) hepatectomized and initiated 24 h later with a single dose of NDEA ip. Five weeks later the rats were administered TCDD in corn oil by sc injection (2 ml/kg) once per week for 20 weeks; controls received corn oil only. Additional groups (five animals/dose) of nonhepatectomized, non-NDEA treated rats were identically treated. The total doses were 0, 0.17, 1.7, 17, and 170 (Han/Wistar only) µg/kg bw. A loading dose, five times higher than the consecutive 19 maintenance doses was given in order to rapidly achieve the kinetic steady state. Daily doses were then calculated on the basis of the maintenance dose which corresponded to calculated doses of 0, 1, 10, 100, and 1000 ng/kg bw/day. Rats were observed daily and weighed on a weekly basis. At termination, the rats were anaesthetised with CO2/O2 (70/30%). Blood samples were drawn from the left ventricle, and the rats were exsanguinated by cutting the aorta.
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Retinoid analyses.
Apolar retinoid analyses were carried out in duplicate on liver and kidney tissue from control and TCDD-treated partially hepatectomised/initiated and nonhepatectomised/uninitiated animals as described previously (Nilsson et al., 2000). Briefly, liver and kidney homogenates were extracted in diisopropyl ether and separated on a Nucleosil C18 5-µ HPLC column (Macherey-Nagel, GmbH, Germany) using an ethanol:water (90:10 v/v) mobile phase. Retinol, retinyl acetate, retinyl palmitate, and retinyl stearate were detected with a JASCO 821-FP fluorescence detector (
ex = 325 nm,
em = 475 nm). On the basis of limited availability of tissue samples in some nonhepatectomized groups and results indicating no major differences between partially hepatectomized groups and nonhepatectomized groups for liver or kidney retinoids (Figs. 1a and 1b), further analyses were conducted in tissues from partially hepatectomized animals. Liver, kidney, and plasma retinoids were extracted and analyzed as recently reported by Schmidt et al. (2003a)
. Briefly, 300 mg of tissue was homogenized in water (1:1, w/w) and extracted into 1.6 ml isopropanol. After shaking and centrifugation the supernatant was mixed with 3.2 ml chloroform. The separation of polar and apolar retinoids was achieved by solid-phase extraction using an aminopropyl phase. Polar retinoids were analyzed on a Spherisorb ODS2 column (2.1 x 150 mm, 3-µm particle size, Waters, Eschborn, Germany) using a binary gradient. The gradient was formed from eluent A, 60 mM ammonium acetate and methanol (1:1, v/v) and eluent B, pure methanol. Polar retinoids were detected with an UV detector at 340 nm. Apolar retinoids were separated on a J'sphere ODS-H80 column (4.6 x 150 mm, 4-µm particle size, YMC Schermbeck, Germany). The gradient was formed from eluent A, methanol and acetonitrile (85:15, v/v), and eluent B, chloroform and acetonotrile (1:1, v/v). Apolar retinoids were detected at 325 nm.
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Data analyses.
All statistical analyses were conducted using SigmaStat statistical software (Jandel Scientific, Erkrath Germany). Data reported are the arithmetic mean ± standard deviation (SD) for individual groups of surviving animals. For comparisons between groups, data that passed tests for homogeneity of group variance (Levene median test) were analyzed using one-way analysis of variance (ANOVA). In cases of statistically significant differences, the data sets were further analyzed using the least significant difference test (LSD). If the variances were heterogeneous, comparisons were made using the nonparametric Kruskal-Wallis one-way ANOVA rank sum test followed by Dunnett's test for multiple comparisons.
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RESULTS |
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DISCUSSION |
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TCDD exposure decreased hepatic all-trans-RA concentrations to 39 and 54% of control values in Long-Evans rats at 10 and 100 ng/kg bw/day, respectively (Table 2). This is the first report of decreased hepatic all-trans-RA concentrations following TCDD exposure in the rat and contrary to a previous single-dose TCDD study that showed increased liver all-trans-RA concentrations (Schmidt et al., 2003b). It maybe that different dosing regimens and/or dietary vitamin A content could explain the dichotomous results in the two studies. Notably, decreased hepatic all-trans-RA concentration was not as sensitive as that of depleted hepatic retinyl ester and retinol levels. Thus hepatic retinol concentration was decreased to about 45 µg/g (approximately 160 nmol/g) in the Long-Evans strain before all-trans-RA concentrations were altered (Table 2). These results imply that hepatic all-trans-RA concentration is strictly controlled following TCDD exposure and declines when there is insufficient retinol to maintain normal retinoic acid synthesis. Interestingly, no consistent differences in hepatic retinoic acid concentrations were seen in mice 7 or 28 days after exposure to single doses of 50 or 250 µg/kg bw TCDD (Högberg, 2003
), suggesting prominent species differences in hepatic all-trans-RA metabolism following TCDD exposure. At present, an explanation for these differences is not readily apparent, but divergences between species in hepatic all-trans-RA concentrations may lead to different responses in all-trans-RA mediated gene transcription.
The concentration of 9-cis-4-oxo-13,14-dihydro-RA was decreased approximately 60% in the liver of both strains at 1 ng/kg bw/day (Table 2). In contrast to all-trans-RA, 9-cis-4-oxo-13,14-dihydro-RA concentration in liver, serum, and kidney has been shown to vary markedly dependent upon vitamin A intake in the mouse (Schmidt et al., 2002). Concentration of 9-cis-4-oxo-13,14-dihydro-RA was markedly decreased in the liver and plasma, but increased in the kidney. At present, the mechanisms of in vivo synthesis and metabolism remain unknown, although it has been speculated that the 9-cis-4-oxo-13,14-dihydro-RA biosynthesis site is likely to be the liver, possibly from all-trans-RA, 9-cis or 9,13-di-cis-retinol precursors (Schmidt et al., 2002
). Nevertheless, the apparent absence of the metabolite in the plasma and its appearance in the kidney at higher doses following TCDD exposure would suggest in situ synthesis of 9-cis-4-oxo-13,14-dihydro-RA in the kidney, perhaps as a consequence of filtration of retinol and/or retinoic acid from the plasma. Whether 9-cis-4-oxo-13,14-dihydro-RA has an important biological function or is an inactive derivative of vitamin A is presently unknown and requires synthesis of the metabolite in sufficient quantities for biological testing. However this study, which showed that 9-cis-4-oxo-13,14-dihydro-RA concentration is dose-dependently and markedly decreased in liver and plasma of both strains following TCDD maintenance doses of 1 ng/kg bw/day, demonstrates that it is a very sensitive marker of TCDD exposure in rats. This result was consistent with an earlier single-dose exposure study in male Sprague-Dawley rats that showed markedly decreased 9-cis-4-oxo-13,14-dihydro-RA concentration in liver (Schmidt et al., 2003b
). For comparative purposes, for instance, at 1 ng/kg bw/day CYP1A1/2 induction as measured by the dealkylation of ethoxyresorufin was 23% (16-fold compared to control) and 7% (27-fold compared to control) of maximum values recorded in the Long-Evans and Han/Wistar rats, respectively (Viluksela et al., 2000
). Other retinoic acid metabolites, including 9-cis-RA, were below detection limits in the liver, consistent with a previous study that failed to detect 9-cis-RA following administration of radiolabeled retinol to vitamin A deficient rats (Werner and DeLuca, 2001
).
Plasma Retinoids, Thyroxine and Vitamin D
Plasma retinol concentrations were increased in a dose-dependent manner; increases were, however, significant at 10 ng/kg bw/day in Long-Evans rat and 100 ng/kg bw/day in the Han/Wistar strain (Table 3). At the high dose in both strains, plasma retinol concentrations were increased to about 23 fold of those observed in control animals, demonstrating that long-term TCDD exposure substantially alters plasma retinol concentrations. These data are consistent with a previous study in Sprague-Dawley rats that showed increased plasma retinol concentrations from 47 ng/kg bw/day TCDD and 2.4-fold increases compared to controls at 1024 ng/kg bw/day (Van Birgelen et al., 1995). The mechanisms by which TCDD causes increased plasma retinol concentrations are not known, but have been suggested to involve increased turnover of hepatic retinyl ester storage pools, resulting in a net mobilization of retinoids (Kelley et al., 1998
, 2000
). Interestingly however, following single doses of TCDD, plasma retinol concentrations were not significantly affected in mice, guinea pigs, or hamsters (Hakansson et al., 1991a
). Thus, since depleted hepatic retinoid levels are common to all species, it is likely that currently unknown factors are involved in the mechanism of increased plasma retinol concentrations that are specifically observed in the rat. The 13-cis-RA/9,13-di-cis-RA co-eluting peak was decreased in plasma from 1 ng/kg bw/day in the plasma of Long-Evans rats and 10 ng/kg bw/day in the Han/Wistar strain. Previous investigation of this peak in a single-dose study suggested that the metabolite predominately affected by TCDD was 9,13-di-cis-RA (Schmidt et al., 2003b
). It has been shown that 9,13-di-cis-RA can undergo interconversion with 9-cis-RA (Horst et al., 1995
) and exhibits transactivating activity toward RAR
(Okuno et al., 1999
). At present, the biological significance of TCDD-induced changes in circulating 9,13-di-cis-RA concentration are unclear; however, the 13-cis-RA/9,13-di-cis-RA co-eluting peak, also appears to be a sensitive plasma marker of TCDD exposure in rats.
Plasma FT4 concentrations were significantly decreased from 10 ng/kg bw/day in the Long-Evans strain, which is in agreement with decreased FT4 concentrations that have been reported previously using a similar study design in Sprague-Dawley rats (Sewall et al., 1995). These results, while consistent with a role for altered thyroid function in the toxicity of TCDD, were not suggestive of a significant contribution to strain differences in sensitivity. Altered plasma 25-OH-D3 concentration was observed only at the high dose in the Long-Evans strain, suggesting that altered vitamin D status, at least at the prohormone level, is not observed in the absence of obvious signs of TCDD toxicity in female rats.
Renal Retinoids
Renal retinol concentrations were significantly and more markedly affected at 100-fold lower doses in Long-Evans rats; however, there did not appear to be marked interstrain differences in retinyl ester concentration (Table 4). Similar to increased plasma concentration, increased renal concentrations of vitamin A have not been observed in mice, hamsters, or guinea pigs (Fletcher et al., 2001; Hakansson et al., 1991a
). Increases in renal retinyl ester concentrations in rats following TCDD exposure have been shown to be correlated to increased lecithin:retinol acyltransferase (LRAT) transcription and activity, as well as increased all-trans-RA concentrations (Hoegberg et al., 2003
; Nilsson et al., 2000
). Although the effect of retinoic acid on the transcriptional activity of LRAT has not been directly investigated in kidney tissue, this result suggests that increased retinoic acid concentrations could promote renal retinol esterification through a mechanism involving increased transcription of LRAT. On the other hand, at present it cannot be ruled out that TCDD may have a direct effect on the transcription of renal LRAT in the rat.
Therefore, in conclusion, we have demonstrated for the first time that long-term low-dose TCDD exposure alters liver, kidney, and plasma concentrations of retinoic acid and retinoic acid metabolites in female hepatectomized/NDEA initiated rats. These results therefore largely confirmed results in male Sprague-Dawley rats that showed that single-dose TCDD exposure altered retinoic acid metabolism in liver, kidney, and serum. Furthermore, the novel retinoic acid metabolite, 9-cis-4-oxo-13,14-dihydro-RA, was identified as a particularly sensitive marker of TCDD exposure in liver and plasma, in both a TCDD-sensitive and -resistant rat strain, thereby adding to the database of low-dose effects of dioxin. Future studies are needed to further investigate the dose response of this metabolite at doses below 1 ng/kg bw/day and to further confirm the sensitivity in a nonhepatectomized model following long-term exposure. Together, these marked alterations of both apolar and polar retinoid levels in liver, plasma, and kidney were consistent with a role for retinoid disruption in the toxic effects of TCDD following long-term exposure in rats.
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ACKNOWLEDGMENTS |
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