* Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599-7270; and
U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, Research Triangle Park, North Carolina 27711
Received October 29, 1999; accepted June 28, 2000
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ABSTRACT |
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Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); disposition; body burden; embryo; fetus.
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INTRODUCTION |
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Prenatal exposure to TCDD during critical periods of development causes adverse reproductive and developmental effects in the offspring at doses well below those causing maternal toxicity. Exposure as low as 0.064-µg TCDD/kg in female Holtzman rats, on gestation day (GD) 15, decreased epididymal sperm reserves in male pups, but it produced no overt signs of toxicity in the pups or the maternal animal (Mably et al., 1992). In male offspring, a dose of 1.0 µg TCDD/kg on GD 8 was associated with a persistent reduction in epididymal and ejaculated sperm counts (Gray et al., 1995
). Furthermore, doses as low as 0.20 µg TCDD/kg administered on GD15, in Long-Evans rats, delayed the onset of puberty in the male offspring (Gray et al., 1997a
). In the female offspring, exposure to 0.2 µg TCDD/kg on GD 15 produced malformations in the external genitalia of the female Long-Evans rat pups (Gray et al., 1997a
,b
). A dose of 1.0 µg TCDD/kg on GD 8 to female rat pups produced a broad spectrum of effects, such as malformations in the external genitalia, premature reproductive senescence, enhanced incidence of constant estrous, and cystic endometrial hyperplasia (Gray and Ostby, 1995
).
Recent studies in our laboratory have shown that exposure to 1.15 µg TCDD/kg, during a critical period of organogenesis (GD 8), results in rat fetal tissue concentrations of 2040 pg/g between GDs 9 and 21 (Hurst et al., 1998). At a dose of 0.05, 0.20, 0.80, or 1.0 µg TCDD/kg administered on GD15 there was approximately 5, 14, 38, and 52 pg TCDD/g, respectively, within each of 3 fetal tissues (head, body, and urogenital tract) (Hurst et al., 2000
). On GD 16, maternal body burdens were 31, 97, 523, and 585 ng TCDD/kg following acute oral exposure to 0.05, 0.20, 0.80, or 1.0 µg TCDD/kg on GD15, respectively. Comparisons of results from 2 different exposures during gestation (on GDs 8 and 15) indicate that fetal tissue concentration better predicts the intensity of several adverse developmental effects (reduced sperm counts and delayed puberty in males and alterations in female genitalia) than does the administered dose (Hurst et al., 2000
).
Several studies have investigated the effects associated with low-dose subchronic exposure to TCDD. In a 2-year carcinogenicity study in rats, Kociba and coworkers (1978) concluded that the no-observed-adverse-effect level (NOAEL) was 1-ng TCDD/kg/day. In a multigeneration study, Sprague-Dawley rats that received 10-ng TCDD/kg/day in the diet did not experience adverse effects on fertility; however, there was a significant decrease in fertility in the F1 and F2 generations (Murray et al., 1979). These data were reanalyzed and it was determined that 1 ng TCDD/kg/day was the lowest-observed-adverse-effect level (LOAEL), rather than the NOAEL (Nisbet and Paxton, 1982
). However, it is difficult to predict TCDD's effect on human populations since large pharmacokinetic differences exist between species. The half-life of elimination ranges from 1531 days in the rat (Allen et al., 1975
; Piper et al., 1973
; Pohjanvirta et al., 1990
; Rose et al., 1976
; Wang et al., 1997
). The half-life in adult humans is estimated at 7.6 years (Michalek and Tripathi, 1999
). Even when corrected for lifespan, humans still eliminate TCDD approximately 36 times slower than rodents. In human infants, the elimination of TCDD appears more rapid than in adults and has been estimated at approximately 4 months (Kreuzer et al., 1997
). Because of the large difference in half-lives between species and developmental stages, knowledge of the disposition of TCDD in fetal and maternal tissue of experimental animals may facilitate species extrapolations. Previous studies have examined maternal and fetal tissue concentrations after repeated dosing regimens. For example, in a multigeneration study, Koch and coworkers (1995) examined hepatic and adipose TCDD tissue concentrations in the dams and offspring after a loading dose/maintenance regimen. In addition, reproductive toxicity and fetal tissue concentrations were measured in rats exposed during pregnancy and lactation (Faqi et al., 1998
).
The objective of this study was to determine maternal and fetal concentrations of TCDD after low-dose, subchronic exposure. The doses used in this experiment (1, 10, and 30 ng TCDD/kg/day) were selected to produce similar tissue concentrations as a single dose of 0.05, 0.20, or 1.0 µg TCDD/kg. These acute doses have been shown to cause a variety of adverse effects in developing male and female rat pups (Gray et al., 1995, 1997a
,, b
; Gray and Ostby, 1995
; Mably et al., 1992
). Therefore, tissue concentrations of TCDD were measured in order to understand the toxicokinetic properties of this compound after continual exposure in LE rats and to compare dose-response tissue concentrations following acute versus subchronic exposures. A subchronic dosing regimen was employed so that maternal concentrations of TCDD would achieve steady state. Since human populations are exposed to continuous low doses of this compound, it is important to understand the toxicokinetics of TCDD in animal models after similar exposures.
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MATERIALS AND METHODS |
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Animals and treatments.
Eight-week-old, time-pregnant LE rats (200300g) were obtained from Charles River Breeding Laboratories (Raleigh, NC) on GD12. Animals were housed individually in clear-plastic cages with hardwood bedding (Beta Chips, Northeastern Products, Warrensburg, NY). Animals were maintained during pregnancy on Laboratory Rodent Diet (#5001, PMI Feeds, Inc., St. Louis, MO) and unpurified tap water ad libitum in a room with a 12:12-h photoperiod and a temperature of 2024°C with a relative humidity of 4050%. Litters were randomly reduced on PND 0 to 4 males and 4 females, when possible. Pups were weaned on PND 21 and were housed in unisexual groups. At 5 weeks of age, the dosing regimen was begun.
Experimental design and treatments.
Three to 6 female rats were assigned to each time point and dose group. Rats received an oral dose of 1, 10, or 30 ng [3H]TCDD/kg in 5 ml corn oil/kg, 5 days/week for 13 weeks. At the end of 13 weeks, animals were mated and dosing continued every day (sperm positive, GD0). For neonatal time points, dosing to the dam continued from parturition to day of sacrifice. Dams from each time point and dosing group were anesthetized with CO2 on GDs 9, 16, and 21 or PND 4, and blood was removed via cardiac puncture. Animals were terminated by cervical dislocation while under anesthesia. The following maternal tissues were removed and weighed: liver, adipose, thymus, muscle, and skin (ears). On GDs 9, 16, and 21, 4 fetuses from each litter were randomly selected, to determine the concentration of TCDD localized in the entire fetus. The remaining fetuses were subdivided into urogenital tract, liver, head, remaining tissue (body), and placenta. On PND 4, the following pup tissues were removed: liver, lung, kidney, and thymus. At this time point, there was not enough adipose or muscle to dissect for a measurement of TCDD concentration.
Oxidation and quantitation of samples.
Tissues were oxidized using a Packard 307 Sample Oxidizer with an Oximate 80 Robotic Operator (Packard, Downers Grove, IL) and analyzed on a Beckman Model LS6000 LL liquid scintillation spectrometer using Monophase S. Previous studies from our laboratory indicated that >95% [3H]-TCDD present in tissues is recovered as parent compound (Kedderis et al., 1991).
Data analysis.
For calculation of percentage total dose, tissue volumes for adipose, muscle, and skin in GD 9, GD 16 and GD 21 rats were experimentally determined as described (Hurst et al., 1998). Although tissue volumes for adipose, muscle, and skin were not determined for PND 4, the values were assumed to be similar to values obtained on GD 9. For all time points, blood mass was assumed 7.4% of body weight (International Life Sciences Institute, 1994
). The data was analyzed in the following dose metric units: percent dose/tissue, percent dose/g tissue, ng TCDD/tissue and ng TCDD/g tissue. Maternal body burdens were estimated based on analysis of 3H-TCDD in the following maternal tissues: liver, adipose, skin, and muscle. It was assumed that
90% of the body burden was due to the amount of 3H-TCDD present in these 4 tissues. Maternal body burdens did not include the fetal compartment.
Statistical methods.
Intergroup comparisons were analyzed by a one-way analysis of variance (ANOVA) (Statview, Abacus Concepts, Inc., Berkeley, CA). When statistically significant effects were detected in the overall analysis of variance, means were compared using Bonferroni's test. When data were collected on more than one fetus per litter, the data were analyzed using litter means rather than individual fetus values. Differences between treatment groups were considered significantly different when p < 0.05. All data in the tables are presented as means ± standard deviations.
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RESULTS |
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Gestation day 21.
As on GD9 and GD16, adipose tissue contained the greatest amount (19% of administered dose/tissue), resulting in a concentration of 110 pg TCDD/g (Table 1) after an administered dose of 1-ng TCDD/kg/day. At the same dose, maternal liver contained 78 pg TCDD/g. Again, there is limited evidence of hepatic sequestration at this dose since the liver/adipose ratio is
0.7. However, at higher administered doses, the concentration of TCDD was greater in the liver than adipose tissue. Another tissue containing relatively large amounts of TCDD was the skin. At all doses examined, the skin contained 13% of the administered dose. At doses of 1-, 10-, and 30-ng TCDD/kg/day, the following concentrations were found in skin: 21, 100, and 231 pg TCDD/g, respectively. Maternal blood contained 0.8 pg TCDD/g at the lowest dose and 13.0 pg TCDD/g at the highest dose. These data clearly show a dose-dependent disposition within the dam. For example, the dose-response curve in maternal liver is supralinear, while the TCDD concentration increases in a sublinear manner in all the other maternal tissues (curves not shown). Maternal body burdens (ng/kg) on GD 21 remain unchanged from GD 9 and GD 16 (Table 2
).
Post-natal day 4.
As seen during gestation, adipose contained the greatest amount of TCDD (11% dose/tissue), resulting in a concentration of 138 pg TCDD/g (Table 1). Concentrations in maternal liver ranged from 673382 pg TCDD/g. Concentrations in maternal blood were 0.4, 4.0, and 12.7 pg/g after 1, 10, and 30 ng TCDD/kg/d, respectively. The concentration in maternal brain ranged from 114 pg TCDD/g. There was a trend towards decreasing liver:fat (L/F) ratios with time (Fig. 1
). L/F ratios on PND 4 appear somewhat lower than maternal ratios during gestation, suggesting a redistribution of TCDD. The total amount of TCDD in the dam increased from GD 9 to GD 16, which was likely due to the increase in maternal body weight (Table 2
). Furthermore, the apparent decrease in the amount of TCDD in the dam from GD21 to PND4 may be explained by the loss of body weight due to parturition (Table 2
). Maternal body burdens on PND 4 were 18, 132, and 335 ng TCDD/kg following exposure to 1, 10, or 30 ng TCDD/kg/d (Table 2
).
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Gestation day 16.
A dose of 1-ng TCDD/kg/day resulted in a concentration of 1.3 pg TCDD/g in a single fetus. This increased to 7.2 pg TCDD/g after exposure to 10 ng TCDD/kg/day and 14.8 pg TCDD/g after exposure to 30 ng TCDD/kg/day. Individual fetuses were subdivided into head, body, liver, urogenital tract, and placenta to determine whether TCDD was sequestered within different fetal tissues. At all doses, the concentration of TCDD was similar in fetal head, body, liver, and urogenital tract and averaged 1.4, 7.8, and 16.4 pg/g tissue following exposures of 1, 10, and 30 ng TCDD/kg/day. However, placental TCDD concentrations were significantly greater than in several of the other fetal tissues (Table 3). An individual urogenital tract contained 0.00006% of the administered dose (1.4 pg TCDD/g) following repeated doses of 1-ng TCDD/kg/day (Table 3
). Urogenital tracts contained 8 and 19 pg TCDD/g following doses of 10- and 30-ng TCDD/kg/day, respectively.
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Post-natal day 4.
Several tissues were examined to determine the extent of lactational transfer of TCDD to neonatal pups. The following 4 tissues were examined: liver, lung, thymus, and kidney. Comparisons between fetal and post-natal concentrations can be made for the liver. Concentrations in the liver on PND 4 increased by 8.3-, 67-, and 73-fold compared to fetal liver concentrations in animals exposed to 1-, 10-, and 30-ng TCDD/kg/day. At all doses, the pup liver contained the greatest concentration of TCDD. Following 1 ng TCDD/kg/day, a pup liver contained 0.04% of the administered dose (0.16% dose/g), which resulted in a concentration of 50 pg TCDD/g (Table 4). This increased to 960 and 2460 pg TCDD/g following exposure to 10 and 30 ng TCDD/kg/d, respectively. In dams exposed to 1 ng TCDD/kg/day, 0.004% of the dose accumulated in the fetal kidney, resulting in a concentration of 13 pg TCDD/g tissue. At each dose level, concentrations of TCDD in pup lung, kidney, and thymus were similar to the concentration of TCDD in maternal thymus (Tables 1 and 4
). In addition, the concentration of TCDD in a PND-4 pup liver at 10- and 30-ng TCDD/kg/day (960 and 2460 pg TCDD/g) was similar to the concentration in maternal liver at these doses (Tables 1 and 4
).
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DISCUSSION |
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For all tissues examined, the highest concentration of TCDD was in maternal liver and adipose. At the lowest dose (1 ng TCDD/kg/day), liver and adipose contained an identical concentration of TCDD (100 ng TCDD/kg). This indicates there was limited hepatic sequestration at this dose. However, on GD 9 at doses of 10 and 30 ng TCDD/kg/d, the liver-to-adipose ratios were 2 and 4, respectively. The hepatic sequestration at higher doses is likely due to the induction of the TCDD-binding protein CYP1A2 in the maternal liver (Diliberto et al., 1997
, 1999
; Santostefano et al., 1996
).
On GD21, at all doses examined, concentrations of TCDD in fetal liver, head, and urogenital tract were similar. The concentrations of TCDD were approximately 2.4, 14.3, and 33.5 pg TCDD/g following 1-, 10-, and 30-ng TCDD/kg/day, respectively. Faqi and coworkers (1998) were unable to detect any TCDD within fetal liver after a loading dose/maintenance dosing regimen administered prior to mating, during mating, and throughout pregnancy, because the concentration was below their limit of detection (<80 ng TCDD/kg). In the study by Faqi et al. (1998), two weeks prior to mating, female rats received an initial loading dose of 25, 60, or 300 ng TCDD/kg. This was followed by a weekly maintenance dose of 5, 12, or 60 ng TCDD/kg during mating, pregnancy, and throughout lactation. Based on these and other data (Faqi et al., 1998; Neubert, 1992
; Neubert et al., 1991
), the body burden of TCDD at steady-state in rats after a subchronic dosing regimen was estimated to be 30-fold that of the concentration after a single dose. For example, an acute dose of 300 ng TCDD/kg would produce the same concentration of TCDD as a daily dose of 10 ng TCDD/kg. Therefore, the loading dose/maintenance doses used by Faqi (25/5, 60/12, and 300/60 ng TCDD/kg) were assumed to be equivalent to daily doses of 0.8-, 2-, and 10-ng TCDD/kg/day (Faqi et al., 1998
). A significant effect at the lowest dose level (25/5 ng TCDD/kg) on sperm number, daily sperm production, and sperm morphology was reported (Faqi et al., 1998
). This dose is similar to the 1ng TCDD/kg/day dosse used in our study, which resulted in fetal tissue concentrations of approximately 2 pg/g. This indicates that fetal concentrations as low as 2 pg TCDD/g, which were measured in the present study, are associated with adverse effects.
The results of Koch and coworkers (1995), similar to our findings, in which they report that the concentration of TCDD in fetal liver of the F1 generation after a loading/maintenance dose of 250/50 ng/kg, was 708 ± 60 ng/kg on PND 3. Again, an acute dose should be approximately 30-fold greater than that of a repeated daily dose to produce equivalent body burdens. Therefore, to produce similar maternal body burdens, the dose used by Koch and coworkers (250 ng/kg) would be equivalent to a daily dose of 810-ng TCDD/kg/day. This is similar to the 10-ng/kg/day dose used in our study, which produced a TCDD concentration of 960 ± 300 pg TCDD/g in a fetal liver on PND 4.
Ostby and coworkers (1999) examined the developmental and reproductive effects associated with a subchronic dose of 10 ng TCDD/kg/day. This exposure caused a 23% incidence of vaginal thread in the female offspring. Results from our study indicate that the tissue concentration of TCDD in the developing urogenital tract after 10-ng TCDD/kg/day exposure is 8 pg TCDD/g on GD 16 and 18 pg TCDD/g on GD 21. Using a one-compartment pharmacokinetic model with first order elimination of TCDD, the subchronic doses were chosen (1, 10, and 30 ng TCDD/kg/day) to result in similar tissue concentrations on GD16 and GD21 as acute doses of 0.03, 0.30, and 0.90 µg TCDD/kg. Hurst and coworkers (2000) demonstrated that a dose of 0.2 µg TCDD administered on GD15 resulted in a urogenital tract concentration of 9 and 18 pg TCDD/g on GD 16 and GD 21, respectively. As expected, these concentrations are similar to the fetal tissue concentrations produced by a subchronic dose of 10 ng TCDD/kg/day. In addition, these concentrations, after acute exposure (0.20 µg TCDD), were associated with a 27% incidence of vaginal thread after an identical exposure (Gray and Ostby, 1995). This analysis supports the idea that tissue concentration measured during a critical period of development provides a means to assess the magnitude of developmental toxicity associated with TCDD exposure. This is in agreement with the results in which fetal TCDD concentrations accurately predicted the magnitude of adverse effects in prenatally exposed pups (Hurst et al., 2000
). In similar studies, comparable biochemical changes occurred in rats after single acute exposure as after repeated exposure to TCDD and/or mixtures of PHAHs (Li and Rozman, 1995
; Viluksela et al., 1997
, 1998
). These studies support the hypothesis that some of the effects after either acute or subchronic exposure are comparable when the dose is corrected for pharmacokinetics.
An interesting observation was that maternal body burdens stayed relatively constant throughout gestation and the neonatal period, supporting the hypothesis that steady-state conditions had been achieved. However, maternal liver/adipose ratios decreased after birth of the pups, indicating a redistribution of TCDD within the dam. This phenomenon can be explained by the tremendous decrease in maternal body weight due to parturition. Table 2 illustrates that while the maternal body burdens are similar on GD 21 and PND 4, there is a decrease in the amount of TCDD (ng TCDD) within the dam during this time period. The variability in the measurement of TCDD in the dam on PND 4 may be due to differences in litter size. For example, more TCDD may be redistributed via lactation from the dam to the pups in larger, compared to smaller, litters. It is clear that the dam has lost some of the total amount of TCDD due to lactation. Further evidence of the lactational transfer of TCDD is seen in the concentration of TCDD in PND-4 pup liver (Table 4
). The concentrations of TCDD in PND-4 pup liver increased significantly compared to GD-21 livers at all doses examined. The increase in liver concentrations is due in part to increased exposures due to lactation and may also be evidence for the hepatic induction of CYP1A2 in neonates by PND 4 as reported by Borlakoglu and coworkers (1993). In another study, Giachelli and Omiecinski (1987) reported a significant induction of CYP1A2 mRNA in rat pup livers on PND 7 after the dams were exposed to 3-methylcholanthrene. The dose-dependent disposition to PND-4 pup liver was supralinear as compared to the sublinear disposition observed in pup lung, kidney, and thymus. This is additional evidence for the hepatic induction of CYP1A2 as early as PND 4. Similar observations on lactational transfer of TCDD have been reported after a single exposure to 5 µg TCDD/kg on GD 19 in rats (Li et al., 1995
).
The data generated in these experiments are useful in determining whether humans that are exposed to low-dose levels of TCDD may be at risk for adverse effects. Mean human background body burdens for PCDDs/PCDFs/PCBS are approximately 913 ng TEQ/kg (DeVito et al., 1995). There are several studies examining the developmental effects of TCDD and related chemicals in humans. However, these studies do not examine endpoints related to the developing reproductive system, and they are complicated by co-exposures to non-dioxin-like PCBs. Women exposed to PCDD/PCDFs in the Yu-Cheng incident had children with decreased birth weights and delayed developmental milestones (Chen et al., 1992
; Lucier, 1991
; Rogan et al., 1988
; Sunahara et al., 1987
). In addition, penis size is decreased in the exposed children from Yu-Cheng (Guo et al., 1993
). The maternal body burden associated with the exposures and effects observed at Yu-Cheng was 2130 ng TCDD/kg (DeVito et al., 1995
), which is approximately 6-fold higher than the body burdens obtained at the highest dose level in the present subchronic study. Studies from the Netherlands suggest that maternal body burdens slightly above background (16 ng TEQ/kg) are associated with lower birth weight, lower psychomotor scores, and poorer neurological condition (Huisman and Eerenstein et al., 1995a
,b
; Koopman-Esseboom et al., 1994
, 1996
; Patandin et al., 1998
, 1999
). The body burdens at the high end of background are similar to the body burdens in the rats of the 1-ng/kg/day-dose group. In the Netherlands studies, some of these effects were also associated with PCB exposures and it is uncertain whether the effects are due to the dioxins, the PCBs, or the co-exposures.
In the human studies examining the relationship between dioxin and PCB exposure and developmental delays, the focus was on neurodevelopmental and immunological alterations. In rats, maternal body burdens, after continuous exposure to 10 ng TCDD/kg/day, were approximately 100 ng TCDD/kg during gestation. Ostby and coworkers (1999) showed that identical exposure resulted in several developmental outcomes: vaginal thread, infantile viability, and accelerated eye opening. This body burden (100 ng/kg) is approximately an order of magnitude greater than the average background TEQ body burden in the industrialized world. Future studies examining the developmental effects of TCDD in humans should consider endpoints that are markers of reproductive system function.
In conclusion, low-dose, subchronic exposure of TCDD produced very low concentrations of TCDD within the developing fetus, and these concentrations were similar to fetal concentrations after a single dose administered during gestation. Furthermore, maternal body burdens measured during steady-state conditions, after low-dose exposure, provide critical information for risk assessment. This study provides a better understanding of the toxicokinetics of subchronic exposure to low levels of TCDD in pregnant rats and their offspring. Such studies may play an important role in understanding interspecies toxicokinetic similarities and differences and in predicting the risks to humans of low-level, chronic exposure to TCDD.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at the U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Experimental Toxicology Division, Pharmacokinetics Branch, Mail-Drop 74, Research Triangle Park, NC 27711. Fax: (919) 541-5394. E-mail: devito.mike{at}epamail.epa.gov.
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