Exposure of experimental animals to TCDD results in a variety of toxic responses which differ in intensity among various species and strains (Poland and Knutson 1989). Of the many organs/systems affected by TCDD, one of the most sensitive is the immune system (Holsapple 1995). TCDD is a highly toxic compound that produces more severe effects when exposure occurs during development. In the rat and the mouse, perinatal exposure to TCDD has been associated with teratogenicity (Couture et al. 1990), reproductive toxicity (Murray et al. 1979; Mably et al. 1992; Gray et al. 1995), neurobehavioral dysfunction (Thiel et al. 1994), and immunotoxicity (Vos and Moore 1974; Faith and Moore 1977).
The results of TCDD studies in experimental animals are of concern because humans potentially have their greatest intakes of TCDD and related polyhalogenated aromatic hydrocarbons during development. Breastfeeding infants have been estimated to consume 35-53 pg TCDD toxic equivalents/kg body weight/day during the first year of life (Schecter et al. 1994). In comparison, various studies have calculated the adult intake to be in the range of 1 or 2 pg TCDD toxic equivalents/kg/day in Germany (Beck et al. 1989; Fürst et al. 1990), the Netherlands (Theelen et al. 1993), and the United States (Schecter et al. 1994). In one study, a nursing infant was found to absorb 96% of the consumed TCDD, since nearly all of ingested TCDD is absorbed (McLachlan 1993). While nursing represents the predominant source of perinatal exposure to TCDD, transplacental exposure also occurs (Korte et al. 1990; Li et al. 1995).
Perinatal TCDD exposure has been shown to alter a variety of immune functions in rodents. In rats, perinatal TCDD exposure suppresses T cell mitogen responsiveness (Vos and Moore 1974; Faith and Moore1977); skin graft rejection time (Vos and Moore 1974); graft- vs.- host activity (Vos and Moore 1974); and DTH responsiveness (Faith and Moore 1977). Perinatal TCDD exposure has also been shown to produce alterations in rat thymocyte subpopulations (Gehrs and Smialowicz 1997), which are similar to those observed in mice perinatally exposed to TCDD (Holladay et al. 1991; Fine et al.1989).
Early work with perinatal exposure of rats to TCDD (Vos and Moore 1974; Faith and Moore 1977) established that immune responses in the offspring associated with cell-mediated immunity were depressed while those of humoral immunity were not. Vos and Moore (1974) show that TCDD exposure studies were performed (i.e., a pre- and postnatal and postnatal-only TCDD exposure) using female Fischer 344 rats. In the first study, pregnant rats were dosed by gavage with 1.0 or 5.0|mg
TCDD/kg on GD 11 and 18, and then postnatally on PND 4, 11, and 18. Most of the neonates in the 5.0|mg TCDD/kg treatment group died. In the postnatal-only exposure study, nursing dams were gavaged with 5|g TCDD/kg on PND 0, 7, and 14. The PHA LP response in 25-day-old male offspring was reduced in the pre-and postnatally exposed and postnatal-only exposed males at 1.0 and 5.0|mg TCDD/kg, respectively. The graft-vs.-host response was also suppressed in 25-day-old male offspring exposed to 5.0|g TCDD/kg postnatally only. Histopathological examination of the thymuses from 25-day-old male and female rats pre-and postnatally exposed to 1.0|g TCDD/kg, and male and female rats postnatally only exposed to 1.0 and 5.0| g TCDD/kg, had atrophy of the thymic cortex. In addition, these offspring did not display any adrenal hypertrophy, indicating that a stress-induced release of glucocorticoids was not considered responsible for the observed immunosuppression (Vos and Moore 1974).
In a follow-up to the Vos and Moore (1974) study, Faith and Moore (1977) employed the same two TCDD exposure regimens with the exception that in the pre- and postnatal TCDD exposure experiment, pregnant Fischer 344 rats were dosed by gavage with 5.0|g TCDD/kg on GD 18, and postnatally on PND 0, 7, and 14. 39-day-old male and female rats had reduced thymus and spleen weights in both TCDD-exposed groups. At 29 and 59 days of age, both TCDD-exposed groups had suppressed spleen cell LP responses to PHA and ConA. The DTH response to oxazolone was also suppressed in both TCDD-exposed groups at 145 days old. In contrast, there was no difference in the antibody titers to bovine gamma globulin (BGG) between control or TCDD-exposed rats. With the exception of the organ weight data, for the immune function results presented in this study, male and female offspring were grouped together rather than separated by gender (Faith and Moore 1977). Consequently, information relative to potential gender susceptibility to perinatal TCDD exposure was not available.
In a TCDD postnatal lactational exposure study, Badesha et al. (1995) exposed lactating Leeds female rats to TCDD in their diet starting on PND 1 through PND 18. The total administered doses over the 18 days of TCDD dosing were 0.2, 1.0, or 5.0|g TCDD/kg dam body weight. At PND 130, body and organ weights were determined and immune function tests were performed. Body weights were reduced in both male and female offspring at 5.0|g TCDD/kg, while liver and spleen, but not thymus, weights were reduced in male offspring, and only spleen weights were reduced in females at 5.0|g TCDD/kg. Offspring displayed suppressed in vivo T cell-dependent and -independent responses and mitogen induced in vitro production of IL-1 and IL-2. Antibody responses to the T cell-dependent antigen SRBCs, and to the T cell-independent antigens dinitrophenyl (DNP)-Ficoll, trinitrophenyl-lipopolysaccharide (TNP-LPS), and LPS were suppressed by 50% of the maximum (i.e., estimates in the range of 0.3-1.0|mg TCDD/kg for the SRBC, DNP-Ficoll and TNP-LPS antigens and 3.5-3.9|g TCDD/kg for LPS antigen). In vitro production of IL-1 and IL-2, by rat splenic macrophages and lymphocytes from TCDD-exposed offspring in the presence of PHA or Con A, respectively, revealed that suppression of IL-1 production occurred at 0.2|g TCDD/kg while that of IL-2 occurred at 1.0|g TCDD/kg. As in Faith and Moore's (1977) study, male and female offspring were combined for immune function assays in the Badesha et al. (1995) study. Consequently, information relative to potential gender-specific differences in immune system susceptibility to lactational TCDD exposure was not available.
Three studies were performed in which timed-bred pregnant Fischer 344 rat dams were given a single gavage dose of TCDD on GD 14 (i.e., GD 0 = day of vaginal plug). Depending on the study, doses ranged from 0.1 to 3.0|mg TCDD/kg. In the first study (Gehrs and Smialowicz 1997), GD 19 fetuses from the 3.0|mg TCDD/kg maternal exposure group exhibited decreased relative thymus weight and thymic cellularity compared to control rats. There were decreased percentages of immature CD3-/CD4+CD8+ thymocytes and increased percentage of CD3-/CD4-CD8+ thymocytes in these fetuses. Development of thymocytes in the fetal thymus is a sequential and highly synchronized process. Kampinga and Aspinall (1990) found that all rat thymocytes are CD3-/CD4-CD8- on GD 14; by GD 19 most rat thymocytes are still CD3-, but some have differentiated through the CD3+/CD4+CD8+ stage. Fine et al. (1989) and Holladay et al. (1991) observed increased percentages of CD4- CD8- and CD4- CD8+ mouse thymocytes on GD 18 as well as a decreased percentage of CD4+CD8+ thymocytes. Blaylock et al. (1992) used the J11d antigen to determine that the CD4- CD8+ population represented immature thymocytes. Taken together with the decrease in thymic cellularity, these results suggest that TCDD mediates its effects in the fetal rat and the fetal mouse either by blocking maturation from CD3-/CD4-CD8+ to CD3-/CD4+CD8+, by selectively eliminating CD3-/CD4+CD8+ cells, or by accelerating the differentiation of the CD3-/CD4-CD8+ cells. The lack of an increase in CD3+ cells in rats so exposed to TCDD rules out the latter of these possibilities. Whether these alterations are responsible for the immune function effects described below remains to be determined.
The second study (Gehrs et al. 1997) was designed to determine if adult immune function was compromised by GD 14 TCDD exposure and to determine whether transplacental and lactational transfer of TCDD to the pups was critical for immunosuppression. Immune function was assessed in pups born to dams exposed to 3|g TCDD/kg on GD 14 at 14 to 17 weeks of age. The DTH response to bovine serum albumin (BSA) was suppressed in both the TCDD-exposed males and females compared to controls. The LP responses to T-cell and B-cell mitogens and the PFC antibody response to SRBCs, while reduced compared to controls, were not significantly lowered. The latter result is the same as that observed by Faith and Moore (1977) in that the antibody response to BGG was not affected by perinatal TCCD exposure.
A second experiment in this study (Gehrs et al. 1997) involved different groups of timed-pregnant Fischer 344 rats dosed with 1.0|g TCDD/kg on GD 14. One day after birth, litters were cross-fostered to produce control, placental-only, lactational-only, and placental/lactational exposure groups. The DTH response to BSA was assessed in 5-month-old males. In these rats the severity of the suppression of the DTH response was related to the route of TCDD exposure (i.e., placental/lactational > lactational > placental), with suppression occurring only in the males receiving both placental and lactational exposure. These results indicated that the immunosuppressive effect of perinatal (i.e., placental and lactational) TCDD exposure of rats persisted into adulthood and that suppression of the DTH response represents the most sensitive biomarker for TCDD-induced developmental immunotoxicity in this species.
The third study (Gehrs and Smialowicz 1999) was designed to better characterize the suppression of the DTH response by perinatal TCDD exposure. "Persistence" of the DTH suppression was determined by measuring the DTH response to BSA in the offspring (at 4, 8, 12, and 19 months of age) of dams dosed orally with 3.0|mg TCDD/kg on GD 14. TCDD significantly suppressed the DTH response in males through 19 months of age. While the DTH response of females was reduced at 8, 12, and 19 months, significant suppression was observed only at 4 months of age.
In a second experiment of this study (Gehrs and Smialowicz 1999), the lowest maternal dose of TCDD that produced DTH suppression was determined by measuring the DTH response to BSA in the 4- and 14-month-old offspring of dams dosed with 0.1, 0.3, or 1.0|mg TCDD/kg on GD 14. In the males, suppression was observed at a maternal dose as low as 0.1|g TCDD/kg at 14 months of age, while a maternal dose of 0.3|g TCDD/kg was required to cause suppression in the 14-month-old females. Both males and females were more sensitive to the suppression of the DTH response to BSA at 14 months of age than at 4 months of age.
In the third experiment of this study (Gehrs and Smialowicz 1999), a comparison was made between the DTH response to BSA and that of keyhole limpet hemocyanin (KLH) in 5-month-old male offspring of dams dosed with 3.0|g TCDD/kg on GD 14. The DTH response to both antigens was equally suppressed by GD 14 TCDD exposure compared to controls. The contact hypersensitivity (CHS) response to dinitrofluorobenzene (DNFB) was also suppressed at 3.0|g TCDD/kg in a more recent study (unpublished observation). Phenotypic analysis was performed on thymus and lymph node suspensions from the DTH/BSA offspring. Significant effects in the thymus included an increased percentage of (ga TCR+ cells and a decreased percentage of (ap TCR+/CD4-CD8- and MHCI- MHCII- cells. In the popliteal lymph node draining the BSA-injected footpad, there was a decreased percentage of (ap TCR+ and MHCI-MHCII- cells and an increased percentage of MHCI+ cells. While phenotypic analysis identified differences in subsets of thymocytes and lymph node cells between control and TCDD exposed offspring, no clear correlations were established between altered subpopulations and suppressed DTH responses.
The results of these three studies indicate that suppression of the DTH response associated with perinatal TCDD exposure is "persistent" throughout adulthood, occurs at a low dose (i.e., 0.1|g TCDD/kg), and is more pronounced in males than females. Both placental and lactational TCDD exposure of the pups is required for suppression of this immune response. While exposure of adult male rats leads to suppression of the DTH response to KLH, a dose of 90|g TCDD/kg is required to produce this immunosuppression (Fan et al., 1996). These data indicate that suppression of the DTH response by TCDD administration during immune system development of the rat requires a TCDD dose that is almost three orders of magnitude lower than that required to suppress this response in adult rats, and that administration of this TCDD dose during this period of development results in "persistent" suppression. These findings provide evidence of two critical criteria (i.e., low dose and "persistent" effect) for labeling the developing immune system of the rat as a very sensitive period for the initiation of immune function impairment by TCDD.
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