Environ. Sci. Technol. 2009, 43, 7946–7951
Effects of Dioxins, PCBs, and PBDEs on Immunology and Hematology in Adolescents M A R I K E M . L E I J S , †,‡ J A N N A G . K O P P E , § KEES OLIE,‡ WIM M.C. VAN AALDEREN,† P I M D E V O O G T , ‡,| A N D G A V I N W . T E N T U S S C H E R * ,⊥ Department of Paediatrics and Neonatology, Emma Children’s Hospital Academic Medical Centre, Amsterdam, Netherlands, Institute for Biodiversity and Ecosystem Dynamics, IBED/ESS, University of Amsterdam, Netherlands, Ecobaby Foundation, Loenersloot, Netherlands, KWR Watercycle Research Institute, P.O. Box 1072, 3430 BB Nieuwegein, Netherlands, and Department of Paediatrics and Neonatology, Westfriesgasthuis, Maelsonstraat 3, 1624 NP Hoorn, Netherlands
Received May 25, 2009. Revised manuscript received August 1, 2009. Accepted August 7, 2009.
Dioxins and PCBs are environmental pollutants, proven to be immunotoxic. In the period 1987-1991 a cohort of mother-baby pairs was initiated to detect abnormalities in relation to dioxin levels in the mother’s milk. At birth and at follow-up at 8-12 years, immunological and hematological effects were seen, prompting us to perform a new follow-up during adolescence. In addition, we assessed the immunological and hematological parameters in relation to current levels of PBDEs and PCBs. In the Netherlands, the pre- and postnatal exposure to dioxins have been studied prospectively since 1987. Venapuncture was performed to assess hematological (Hemoglobin, thrombocytes, thrombopoietin) and immunological (leukocytes, leukocyte differentiation) parameters and the current serum levels of dioxin, dioxinlike(dl)-PCBs and PBDEs. A decrease in the number of polymorphic neutrophils was found in adolescents with higher dl-PCBs in their serum (p ) 0.021). No relation with total leukocytes, thrombocytes, hemoglobin, or thrombopoietin levels was seen. Similarly, we found no relation between prenatal, nor current, dioxin levels and the hematological and the immunological parameters determined. The ΣPBDEs were negatively associated with the number of lymphocytes (p ) 0.01) and positively associated with the hemoglobin concentration (p ) 0.003). These effects on the innate immunity by current levels of dl-PCBs and on the adaptive immunity by PBDEs are disconcerting, especially as the dlPCB (0.04-7.8 WHOTEQ pg/g lipid, mean: 2.2 WHOTEQ pg/g lipid) and ΣPBDE levels (mean 14.0 ng/g lipid, including one outlier with a sum of 73.6 ng/g lipid) were not high.
* Corresponding author phone: + 31 229 257535; fax: +31 229 257951; e-mail:
[email protected]. † Emma Children’s Hospital Academic Medical Centre. ‡ University of Amsterdam. § Ecobaby Foundation. | KWR Watercycle Research Institute. ⊥ Westfriesgasthuis. 7946
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Introduction Dioxins (PCDD/F), and especially 2,3,7,8-tetrachloro-dibenzoF-dioxin are well-known immunotoxicants. Effects on the cell-mediated and humoral-mediated immunity have been seen in animals (1). An important target organ of dioxin immunotoxicity is the thymus, where maturation of Tlymphocytes takes place. Atrophy and suppression of the thymus-dependent immunity have been noted (2). Administration of dioxins during the perinatal period has proven to cause severe immunosuppression in rats and mice (3). Pluim et al., in the same group of children as the current cohort, found a reduced number of polymorphic neutrophils in relation to prenatal and lactational dioxin exposure; in the same study thrombocyte counts appeared to be significantly decreased, in relation to increasing lactational dioxin exposure (4). The pronounced effect on the number of polymorphic neutrophils around birth, an effect on the innate immunity, was confirmed in another study in Rotterdam (5). However, these effects were no longer evident at the 30month follow-up (6). Follow-up of our cohort during childhood revealed a persistently decreased number of thrombocytes, with a significant increase in thrombopoietin, as well as a possible decrease in allergy. We found the outcomes suggestive of a toxic effect at stem cell level. The lymphocyte counts showed an increased CD4+ T-helper and increased CD45RA number in relation to perinatal PCDD/F concentration at prepubertal age (7). In our ongoing follow-up study of the development of children, now in their adolescence, with documented perinatal dioxin exposure, we again measured hematological and immunological parameters and compared these to prenatal, lactational, and current serum PCDD/Fs, dioxin-like polychlorinated biphenyls (dl-PCBs) and polybrominated diphenyl ethers (PBDEs).
Materials and Methods Study Population. This study is part of a longitudinal cohort study of currently 14-19 year old children, studied during their neonatal (n ) 60) (8), toddler (n ) 60) (9), and prepubertal period (n ) 41) (10). All 33 children (18 girls and 15 boys) participating in the current follow-up were born in the Amsterdam/Zaandam area. Twenty-five of the children are still inhabitants of the region. PCDD/F exposure was determined shortly after birth in the breast milk of their mothers. Of the total cohort of 41 subjects who participated in the prepubertal study, one subject was excluded from the current follow-up because of a Ewing sarcoma and one was excluded from this part of the study because of an extra Y chromosome (XYY). Five subjects declined to participate in the new follow-up, two could not be traced. One participant of the current follow-up study did not participate in the prepubertal study round. Of the 33 examined adolescents 2 refused to undergo vena puncture and 2 refused a repeated puncture after blood clotting in the first needle. The study was approved by the institutional medical ethics committee. All participants of the study and their parents signed an informed consent. Laboratory Analyses. For measurements of the current PCDD/F, dl-PCB, and PBDE serum concentrations, 30 subjects underwent vena puncture, following a fasting period of at least four hours. Serum was obtained from the blood samples and the samples were stored at -20 °C until analysis. Perinatal PCDD/F levels and current serum levels of PCDD/ Fs, dl-PCBs, and PBDEs were measured in a contaminationfree laboratory at the Department of Environmental Chem10.1021/es901480f CCC: $40.75
2009 American Chemical Society
Published on Web 08/27/2009
TABLE 1. Mean Age, Dioxin, dl-PCB, and PBDE Exposures age (years) n ) 33 prenatal PCDD/F exposure ITEQ (pg/g lipid) n ) 33 lactational PCDD/F exposure ITEQ (ng) n ) 33 current serum PCDD/F WHOTEQ (pg/g lipid) n ) 28 current serum dl-PCBs WHOTEQ (pg/g lipid) n ) 29 current serum PBDE (ng/g lipid) n ) 18
mean
range
15.0
14.0-18.7
32.6
8.7-88.8
66.9
4.34-279
2.2
0.4-6.1
2.2
0.04-7.8
13.9
4.9-73.6
istry of the University of Amsterdam. Concentrations of the 19 most toxic dioxin congeners (7 PCDDs and 12 PCDFs) and the concentration of 3 dl-PCBs (nos. 77, 126, 169) and 8 PBDEs (nos. 28, 47, 85, 99, 100, 153, 154, and 183) were determined. The concentrations of PCDD/Fs and dl-PCB congeners were expressed in TEQ pg/g lipid using the new WHO TEF values (11). The prenatal and lactational TEQ values are expressed in international toxic equivalents (I-TEQ) as used in 1991. Levels of leptin, glucose, insulin, lipid spectrum, immunological parameters, hematological parameters, and thyroid parameters were measured in the serum of the adolescents. In the serum samples, separation of the PCDD/Fs, dlPCBs, and PBDEs was performed using an activated carbon column. The PCDD/F fraction was cleaned-up using silver nitrate on silica gel and activated aluminum oxide. PBDE fractions were purified using acid-base silica columns and activated aluminum oxide. After concentrating the sample, identification, and quantification of dioxins and dl-PCBs was done using hr-GC/h-MS. PBDEs were determined by hrGC/lr-MS. As an internal standard, a mixture of 13C-labeled PCDD/Fs, dl-PCBs, and PBDEs was used. More detailed information about the analyses has been published elsewhere (12). The prenatal PCDD/F exposure was previously measured in the mother’s milk 3-4 weeks after birth, representing the dioxin exposure before birth. The lactational PCDD/F exposure represents the levels found in breast milk multiplied by the total breast milk intake (13). The total duration of breast feeding varied from 3 to 88 weeks. Haematological parameters were assessed by measuring hemoglobin and thrombocytes in the clinical chemical laboratory in the Zaans Medical Centre in Zaandam. The amount of trombopoietin was assessed in the Algemeen Medisch Laboratorium in Antwerp. Immunological parameters were assessed measuring the number of leukocytes and the differentiation in the clinical chemical laboratory in the Zaans Medical Centre in Zaandam. Statistical Analyses. For statistical analyses the nonparametric Spearman’s correlation coefficient was calculated using the software package SPSS. The level of significance was 5%. Statistical analysis was performed with and without exclusion of one outlier in the level of sumBDEs.
Results Haematology. The age of the cohort and the amount of perinatal and current dioxin exposure, as well as the current dl-PCB and PBDE levels in serum, are shown in Table 1. There was no significant relation between prenatal PCDD/F exposure and current serum PCDD/F levels (12). Serum levels of hemoglobin, the number of blood platelets and levels of trombopoietin are presented in Table 2. Exclusion of the outlier had no effects on the significance of the outcomes.
TABLE 2. Serum/Blood Parameters: Mean Values and Ranges Observed n = 30
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thrombocytes (10 /l) hemoglobine (mmol/L) thrombopoietine (E/ml) HbA1C (%) leukocytes (109/l) polymorphic neutrophils (109/l) lymphocytes (109/l) monocytes (109/l) eosinophils (109/l) basophils (109/l)
mean
range
268 8.47 18.9 5.60 6.94 4.03 2.12 0.49 0.25 0.04
156-352 6.70-9.70 6.00-41.0 5.00-6.10 3.40-10.4 1.71-7.49 1.04-3.44 0.32-0.86 0.05-0.69 0.00-0.21
Using the nonparametric Spearman’s correlation coefficient, we found a positive relationship with the hemoglobin level and the current serum PBDE concentration (Figure 1; p ) 0.003), without exclusion of the outlier p ) 0.017. Congener specific analysis of the sum of PBDEs showed that the main contributors to this relation were PBDE congeners 85 (p ) 0.032) and 153 (p ) 0.066). No associations with PCDD/Fs or dl-PCBs were evident. Contrary to the findings during infancy and at the age of 8-12 years, no association was seen between the prenatal or current dioxin, dl-PCB or PBDE exposures and the current thrombocyte count and thrombopoeitin levels. Immunology. Effects on the immune system were evaluated using the leukocyte and differentiation counts. Mean values and ranges of the outcomes are shown in Table 2. A negative effect on polymorphic neutrophils was found in adolescents with higher current dl-PCB levels in their serum (Figure 2; p ) 0.021). In the neonatal period this negative effect was seen with prenatal PCDD/F exposure. No relationship between neutrophils and perinatal or current dioxins or PBDE levels in serum was seen. The PBDEs showed a negative relationship with the number of lymphocytes (Figure 3; p ) 0.01),without exclusion of the outlier p ) 0.016. Congener specific analysis of the sum PBDEs showed that the main contributors to this association were PBDE congeners 183 (p ) 0.008), 154 (p ) 0.009), and 85 (p ) 0.03).
Discussion All cellular elements of blood, such as red blood cells, leukocytes, and blood platelets, derive from the same progenitor or precursor cells, the hematopoietic stem cells in the bone marrow. In the bone marrow differentiation takes place, under influence of interleukin and growth factors, to myeloid progenitors, the precursor of the different types of leukocytes, erythrocytes and the megakaryocytes, and the common lymphoid progenitor, which gives rise to the lymphocytes (14). Under influence of other growth factors the stem cells differentiate to erythroblasts and megakaryocytes. This is regulated by hemopoietic growth factors (HGF). One of these factors, erythropoietin, is produced in response to hypoxia in the peritubular adventitial cells of the kidney. Furthermore, inhibiting factors also play a role (15). Haematology. We found a positive relation between serum hemoglobin (Hb) content and the serum ΣPBDEs (p ) 0.003). Erythrocytes and thrombocytes have, during maturation, a common pathway of precursors, before they differentiate into erythroblasts and megakaryocytes. The differentiation toward erythroblast production can be influenced by delta-aminolaevulinic acid (16). An increase in delta-aminolaevulinic acid is found after PCBs, polybrominated biphenyls (PBBs) and lead intoxication (17). This may be a mechanistic explanation of our findings with PBDEs. VOL. 43, NO. 20, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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FIGURE 1. Hemoglobine concentrations versus current serum levels of ΣPBDEs A positive relationship between the ΣPBDEs (ng/g lipid) and hemoglobine concentration (mmol/L) was seen (p ) 0.003).
FIGURE 2. Concentration of segmental neutrophils in blood/serum vs current serum levels of dl-PCBs A negative relationship was seen between the current serum dl-PCBs (TEQ pg/g lipid) and the number of segmental neutrophils (109/L) (p ) 0.021). Another possible explanation is a higher production of erythropoietin in the kidney. A toxic effect on the kidney has 7948
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been documented in mice and rats, following exposure to dioxins (18). Cytoplasmic changes in kidney epithelial were
FIGURE 3. Concentrations of Lymphocytes in serum and current serum levels of ΣPBDEs. A negative relationship was seen between the number of lymphocytes (109/L) and ΣPBDEs (p ) 0.01). found after a dose of 80 mg/kg-bw PBDEs per day in a shortterm repeated-dose toxicity study (19). A study in mink showed a lower hematocrit in association with a mixture of PBDEs (20). The study did not evaluate Hb. Immunology. Human immunity can be divided into the innate immune system and the adaptive immune system. The latter is highly specific to invading micro-organisms and has a memory function. The innate immunity contributes to host defense immediately after infection, before the adaptive immunity becomes active. Natural killer cells, monocytes, macrophages, and polymorphic neutrophils form the innate immunity. There are indications that PCDD/Fs and dioxin-like PCBs negatively influence the innate immunity. In our study a negative effect was found on the number of polymorphic neutrophils (Figure 2, p ) 0.021) in relation to dl-PCBs, similar to the dioxin relation in the neonatal period. PCBs and some of the BFRs induce formation of ROS (reactive oxigen species) in neutrophil granulocytes, in animal studies. This takes place primarily through phosphorylation and subsequent activation of the NADPH oxidase, and has an adverse effect on the neutrophil granulocytes (21). One study, however, found that coplanar congeners with high affinity for the Ah receptor (AhR, also known as the dioxin receptor) do not activate neutrophils to produce O2- and may inhibit this response (22). Generally, dioxin effects on the immune system are dependent on signaling through an intracellular receptor known as aryl hydrocarbon receptor (AhR) (23). Many of the specific effects of PCDD/Fs and dl-PCBs on the immune system are also dependent on the modulation that the active form of the AhR can exert on the NF-κB signaling pathway, and the regulation of genes that code for growth factors, cytokines, and pro-apoptotic and antiapoptotic factors. The NF-κB signaling pathway is complex, and immune system
functions depend on a tight regulation of cellular proliferation, growth, survival, and apoptosis in many physiological situations, like ontogenic development, adaptive cellular and humoral immune response, inflammation, and innate immune responses (24, 25). Interestingly, a recent finding shows the AhR is selectively expressed on a relatively new CD4 effector T cell subset, the Th-17 subset. However, the Th-17 cells have been found to be responsible for many autoimmune syndromes, such as multiple sclerosis, rheumatoid arthritis, and myocarditis. Therefore stimulation of the AhR on these cells may greatly enhance autoimmune pathology (26). In our cohort, when studied at prepubertal age (8-12 years), we found abnormalities in T-lymphocytes in relation to prenatal PCCD/F exposure (increase in CD4+). Similarly, the Rotterdam preschool study showed the number of T-cells to be increased, together with lower antibody levels against measles and a higher prevalence of chickenpox at 18 months, with prenatal dioxin TEQ, while at 42 months the relation was with ΣPCBs. Both PCBs and dioxins are known to change the kinetics of thymocyte maturation and thymus atrophy in in vitro studies. In Japanese breast-fed infants the CD4+, CD8+ and ratio between the two lymphocyte subsets was shown to be positively influenced by the amount of dioxins consumed (27). A study of progenitor cells (PC) exposed to a single dose of the PCB mixture Aroclor 1248 showed the production of a factor(s) that activates neutrophils, stimulating them to damage PC populations in culture (28). We also found a negative association between the lymphocyte counts and PBDEs (Figure 3; p ) 0.01). The toxicity of some PBDE congeners may be compared with phenobarbital. This antiepileptic medicine may lower lymphocytes counts (29). An in vitro study in human VOL. 43, NO. 20, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
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lymphocytes, however, showed no effects of PBDEs on the proliferation and immunoglobulin synthesis (30). A Chinese study demonstrated negative effects on the T-lymphocytes, in the offspring of PBDE-209 exposed rat. Furthermore, significant differences in the weight of the immunity organs was noted between the exposure and control groups (31). A study in mice found signs of immunotoxicity after oral exposure to DE-71 (a mixture op PBDEs). The plaque-forming cell response to sheep erythrocytes (SRBC) and natural killer cell (NKC) activity was decreased and there was a decreased thymus weight after suppletion of this PBDE mixture (32). A study on DE-71 exposed mink revealed significantly larger spleen, adrenal, and liver masses than control mink. Spleens of mink exposed to 10 ppm of DE-71 had significantly increased germinal center development and incidence of B-cell hyperplasia. Percentage neutrophils increased and percentage lymphocytes decreased significantly in mink in the higher two dosage groups (20). It is of great concern that not only the rather high dioxin and PCB levels in the neonatal period, but also the current levels of dl-PCBs and PBDEs have persistent and/or recent effects on respectively the innate and adaptive immunity. To our knowledge, this is the first study showing effects of PBDEs on the human immune and hematological system in adolescence. A lower number of polymorphic neutrophils of the innate immunity were seen in our cohort, during the neonatal period with PCDD/F exposure and in puberty with dl-PCB exposure. PBDEs have a negative effect on the number of lymphocytes. We present novel findings, however the size of the cohort is an important limitation. Studies to confirm our findings in a larger cohort, and to assess the longer term consequences of the exposures, are warranted.
Acknowledgments We thank the participants of the study, and their parents, for their time, enthusiasm, and cooperation; Dr. J. Oosting for his help with the statistics; and P. Serne´, F. vd Wielen and J. Parsons of the laboratory of the Institute for Biodiversity and Ecosystem Dynamics and T. van Teunenbroek of The Netherlands Ministry of Housing, Spatial Planning and the Environment. We are indebted to Matthijs Westra, M.D. and the Zaans Medical Centre for their help in performing the study. The paper was supported by E.C. grant: HENVINET 037019.
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