Abstract  Hamsters and Han/Wistar (Kuopio; H/W) rats show peculiarly selective responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). They are extremely resistant to its acute lethality but sensitive to, e.g. , enzyme induction. The biological effects of TCDD are mediated by the AH receptor (AHR). Recent studies on H/W rat AHR discovered a remodelled transactivation domain which appears to be critical for the TCDD resistance of these animals. Here, molecular cloning and sequencing of hamster AHR reveals another type of restructured transactivation domain. In hamsters, the functionally pivotal Q-rich region is substantially expanded and enriched in glutamine compared with all other AHRs cloned to date. By contrast, the amino-terminal end is highly conserved, which is in agreement with the H/W rat AHR. Because of the additional material in the transactivation domain, hamster AHR protein is larger than that in rats or mice, but the pattern of AHR mRNA expression in tissues is similar. Copyright 2000 Academic Press.

Abstract  The purpose of this paper is to report on the results of a joint survey of the United States Department of Agriculture (USDA) and the United States Environmental Protection Agency (EPA) on the rate of occurrence and concentration of chlorinated dibenzo-p-dioxins (CDDs), chlorinated dibenzofurans (CDFs), and coplanar polychlorinated biphenyls (PCBs) in the fat of U.S. pork animals. This survey, conducted in 1997, was the first statistically designed national survey of levels of CDDs/CDFs/PCBs in pork animals in the U.S. It was prompted by EPA's Reassessment of Dioxin-Like Compounds and funded from EPA's Dioxin Exposure Initiative. It is the second joint USDA/EPA effort of its kind, the first being a survey of beef back fat. This report has been developed and reviewed by representatives from both EPA and USDA, but has not been externally peer reviewed.

Abstract  Dioxins, including the most toxic congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), exert diverse biological effects in humans and animals. Host resistance, especially to virus infections, is considered one of the most sensitive targets of TCDD-toxicity, while a recent study showed that the vulnerability to TCDD of host resistance to viruses varied form experiment to experiment. Burleson et al. [Fundam. Appl. Toxicol. 29 (1996) 40] reported that a single oral dose as low as 10 ng TCDD/kg increased the mortality of mice infected with influenza A virus. If this value had been adopted as the basis for the tolerable daily intake (TDI) of dioxins, the TDI of 1-4 pg toxic equivalent (TEQ)/kg per day recommended by WHO would have to be lower. In the present study, we used the same experimental protocol described by Burleson et al. to determine whether low-dose TCDD consistently compromises the host resistance of mice infected with influenza A virus. To do so, we investigated the effect of TCDD in the dose range of 0-500 ng/kg on the mortality of virus-infected female B6C3F1 mice. We also investigated the sex- and strain-dependency of host resistance in male B6C3F1 mice and in female C57Bl/6, Balb/c, and DBA/2 mice by administering the same dose range of TCDD. The results showed that TCDD doses up to 500 ng/kg did not increase the mortality of virus-infected mice in any of the strains. Further studies on the mechanism underlying the toxicity of TCDD are needed to assess the risk of exposure to this compound in influenza A virus infection.

Abstract  Dioxins are a class of polyhalogenated aromatic hydrocarbons that induces a wide spectrum of toxic responses in animals. Health effects have been studied intensively, but the detailed molecular mechanisms are quite complex and not yet fully understood. In this study, the effects of model dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on protein modifications such as glycosylation and phosphorylation were extensively studied. Using 2-D electrophoresis, various protein visualizations techniques, protein modification-dependent enrichments techniques and mass spectrometry, we performed comparative proteomic investigations on Chang human liver cells before and after the treatment with TCDD. Many glycoproteins and phosphoproteins were found to be affected by the TCDD treatment. The glycosylations on Cathepsin B, HSP60, the subunit 5 of chaperonin containing TCP1 complex, and Prolyl 4-hydroxylase beta-subunit were increased. Heat shock 70 kDa protein 5 and ATP synthase beta subunit showed enhanced or reduced phosphorylation, respectively. Two microtubule associated proteins, Microtubule-associated protein 1S and ARP1 actin-related protein 1 homolog A showed enhanced tyrosine phosphorylation. The data in this study provide interesting insights on the molecular and biochemical events of TCDD-mediated toxicities.

Abstract  Polychlorinated biphenyls are persistent environmental pollutants that elicit a wide range of effects in humans and wildlife, mediated by the aryl hydrocarbon receptor. 3,3',4,4',5-pentachlorobiphenyl (PCB126) is the most potent congener with relative effect potencies ranging from 0.0026 to 0.857, and a toxic equivalency factor (TEF) of 0.1 set by an expert panel of the World Health Organization. In this study, the hepatic effects elicited by 300 microg/kg PCB126 were compared with 30 microg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in immature, ovariectomized female C57BL/6 mice. Comprehensive hepatic gene expression analyses with complementary histopathology, high-resolution gas chromatograph/high-resolution mass spectrometer tissue analysis, and clinical chemistry were examined. For temporal analysis, mice were orally gavaged with PCB126 or sesame oil vehicle and sacrificed after 2, 4, 8, 12, 18, 24, 72, 120, or 168 h. In the dose-response study, mice were gavaged with 0.3, 1, 3, 10, 30, 100, 300, 1000 microg/kg PCB126, 30 or 100 microg/kg TCDD and sacrificed after 72 h. 251 and 367 genes were differentially expressed by PCB126 at one or more time points or doses, respectively, significantly less than elicited by TCDD. In addition, there was less vacuolization and necrosis, and no immune cell infiltration, despite comparable or higher TEF-adjusted hepatic PCB126 levels. The functional annotation of differentially expressed genes was consistent with the observed histopathology. Collectively, the data indicate that 300 microg/kg PCB126 elicited a subset of weaker effects compared with 30 microg/kg TCDD in immature, ovariectomized C57BL/6 mice.

Abstract  We have previously shown that exposure of mice to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induces activation-like changes in splenic dendritic cells (DC) in the absence of antigen challenge. Since activation of DC reduces their ability to phagocytize antigen, we examined the effects of TCDD on the ability of DC to process and present antigen to antigen-specific T cells and to internalize latex beads. Additionally, the expression of costimulatory and adhesion molecules was examined on DC from TCDD-treated mice injected with allogeneic tumor cells. The ability of DC from C57Bl/6 mice to induce proliferation of keyhole limpet hemocyanin (KLH)-specific 10.5.17 T cells and production of IL-4 was not significantly altered by TCDD exposure, either when KLH was added in vitro or when the mice were injected with KLH prior to DC isolation. In contrast, ovalbumin (OVA) presentation by DC from TCDD-treated Balb/c mice induced enhanced proliferation of OVA-specific D011.10 T cells, although the production of IL-2 and IFN-gamma was not affected. Enhanced in vivo proliferation of adoptively transferred, CFSE-labeled DO11.10 T cells was also observed in TCDD-treated Balb/c mice that were challenged with OVA. TCDD treatment modulated the expression of major histocompatibility complex (MHC) class II, CD24, ICAM-1, CD40, and LFA-1 on splenic DC from C57Bl/6 mice injected with allogeneic tumor cells; however, the effects of TCDD were identical to changes seen previously in nonimmune mice, suggesting that these effects were not antigen-dependent. Finally, TCDD treatment did not affect the ability of splenic DC to internalize latex beads administered in vivo. Taken together, these results suggest that the activation-like changes induced in DC by TCDD do not suppress the ability of DC to process and present antigen, but may enhance their ability to provide activation signals to T cells. This, in turn, may alter the survival of the T cells, the DC, or both, and might lead to dysregulation of the immune response.

Abstract  The cancer incidence data from the Operation Ranch Hand Study are plotted as a function of seven dioxin body burden classifications from zero through modest levels above background. The three significant cancer incidence peaks and three significant cancer incident troughs observed are used to test a model which specifies dioxin activity as both a promoter blocker and a cancer causation agent. There is a significant, 50% reduction in total cancers other than skin at the highest dioxin body burden level compared to background. There is a significant reduction in prostate cancers in Black veterans, but not in White, as a function of increasing dioxin body burden.

Abstract  The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by a structurally diverse range of synthetic and natural chemicals, and it mediates the toxic and biological effects of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The spectrum of chemicals that bind to and activate the AhR signal transduction pathway and the identity of materials containing AhR active chemicals is only now being defined. Utilizing AhRdependent gel retardation and reporter gene bioassays, the screening of extracts of 22 dietary herbal supplements and 21 food products (vegetables and fruits) was performed to identify those containing AhR agonists. Several herbal extracts (ginseng, Fo-Ti, white oak bark, licorice, ginkgo biloba, and black cohosh) stimulated AhR DNA binding and gene expression to levels between 20 and 60% of that produced by TCDD. Although some food extracts (corn, jalapen˜o pepper, green bell pepper, apple, Brussels sprout, and potato) were relatively potent activators of AhR DNA binding (30-50% of TCDD), only corn and jalapen˜o pepper extracts induced AhR-dependent luciferase reporter gene expression. However, dilution of corn, jalapen˜o pepper, bell pepper, and potato extracts dramatically increased their ability to induce luciferase activity, suggesting that these extracts contained AhR antagonists whose effectiveness was overcome by dilution. Overall, these results demonstrate that dietary products can be a major source of naturally occurring AhR ligands to which animals and humans are chronically exposed.

Abstract  An underlying basis of risk assessment is that an equivalent risk for a specified dose metric exists that allows for extrapolation of dose-response relationships between species. To better understand the use of area under the curve (AUC) as a dose metric for complex biological responses following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, a study was designed using a physiologically based pharmacokinetic model in the female Sprague-Dawley rat that would result in equivalent AUCs of total liver TCDD with differing patterns of exposure. In the first group, rats received a high peak dose of 3500 ng TCDD/kg twice per week in the first week followed by a lower TCDD dose of 81 ng/kg twice per week for the remainder of the study. In the second group, rats received a gavage dose of 350 ng TCDD/kg in corn oil twice per week for the study duration of 15 weeks. Age-matched control rats received corn oil as a vehicle control. Placental glutathione S-transferase (PGST)-positive foci were measured in representative liver lobes by immunohistochemistry, as a representative complex biological response resulting from TCDD exposure. The median volume fraction was 0.045% in control rats and was significantly elevated in TCDD treatment groups. However, the volume fraction of PGST-positive foci was significantly higher in the TCDD group given the high peak dose during the first week of TCDD treatment compared with the group receiving the same average daily dose over the study duration: 0.74 versus 0.20%, respectively. These findings suggest that the peak magnitude of TCDD in liver rather than AUC may play a significant role in the induction of complex biological responses by TCDD.

Abstract  The Ah receptor mediates the toxicological responses of 2,3,7,8-TCDD and related compounds. Receptor-deficient animals were shown to be resistant to the toxic effects of dioxin, although there is also evidence for the existence of a receptor-independent pathway for dioxin-induced toxicity. In the cytosol the receptor is present in a non-activated ligand binding conformation. Association with Arnt in the nucleus turns the receptor complex into a ligand activated form. The physiological role of the receptor is not yet understood; however, the conservation of the receptor in a wide range of animal species (including humans) suggests a fundamental role in cellular physiology.

Abstract  2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces aberrant release of gonadotropins, FSH, and LH and blocks ovulation during induced ovarian follicular development in rats by an unknown mechanism. In the current study, TCDD (0, 8, or 32 microg/kg orally) was administered to immature female Sprague-Dawley rats, and synchronous follicular development was induced 24 h later with equine chorionic gonadotropin (eCG, 5 IU s.c.). Both doses of TCDD induced a significant premature increase in serum FSH and LH (P < 0.05) at 12 h post-eCG. This premature gonadotropin surge was facilitated by the administration of a long-acting estradiol (estradiol cypionate, 0.01, 0.1, and 0.5 mg/kg s.c.), whereas the progesterone and cortisol receptor antagonist RU486 (0, 1, and 10 mg/kg s.c.) potentiated the premature release of FSH and LH following TCDD as well. Pentobarbital (32 mg/kg i.p.) administered at 6 or 9 h, but not 0 h, post-eCG ablated the ability of TCDD to stimulate the release of FSH and LH in vivo. TCDD had no significant effect on GnRH accumulation in vitro from immortalized GnRH neuronal (GT1-7) cells and failed to alter the cell number. Transfection of these cells with a rat GnRH promoter-reporter construct revealed no significant acute effect of TCDD on GnRH promoter activity. Aryl hydrocarbon receptor mRNA was not detected in the GT1-7 cells by reverse transcription polymerase chain reaction. TCDD appears to stimulate premature gonadotropin release in the gonadotropin-primed immature rat by interacting with an estradiol- and pentobarbital-sensitive neural signal for GnRH release but not by acting upon the GnRH neuron directly.

Abstract  Polychlorinated dioxins and poly chlorinated dibenzofurans (PCDDs and PCDFs) can be produced by a variety of primary sources. Human exposure occurs primarily via secondary or semisecondary sources such as ingestion of food and drinking water and through dermal contact and inhalation. The primary sources of PCDDs and PCDFs include chemical reactions and thermal and photochemical source. Analyses of archived samples of soil and vegetation show that low levels of PCDDs and PCDFs can be identified in 150-year-old samples; however, these levels have been shown to increase between 1940 and 1986. Mass balance estimates indicate a pronounced difference between the known emissions of PCDDs and aerial deposition, the latter being approximately 10-20 times higher.

Abstract  The biology and physiology of the male as well as female reproductive system is hormonally regulated. Abnormalities in the dynamics of hormone production, metabolism and elimination, as well as their binding to certain target tissues, has been associated with pathophysiological conditions of the reproductive system. Although oestrogens are known to be one of the major hormone groups in regulating the reproductive function and the fertilization process, the cellular and biochemical mechanism or mechanism(s) via which oestrogens induce their effects are still not fully defined. Moreover, in a modern environment we are also exposed to a wide battery of environmental agents which are structurally similar to oestrogens, and termed 'environmental oestrogens'. Because environmental oestrogens have been shown to mimic some of the effects of oestradiol, it has been postulated that these exogenous chemicals may influence or interfere with the oestrogen-dependent reproductive processes, and may be associated with beneficial as well as deleterious effects on the reproductive system. In this regard, two classes of environmental oestrogens have been widely studied, i.e. phyto-oestrogens (plant-derived dietary oestrogens) and xeno-oestrogens (industrial chemicals, including polychlorinated biphenyls, DDT, TCDD, dioxins, etc.). The main focus of this review is to provide an overview on the cellular and biochemical mechanism(s) by which xeno-oestrogens and phyto-oestrogens influence the oestrogen-dependent reproductive functions and induce their deleterious or protective effects on the reproductive system.

Abstract  2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (PCDF) are widespread environmental pollutants. TCDD is well known for its adverse effects on female reproduction when administered acutely to immature or adult rats. It is also known that fetal/neonatal exposure to this compound alters reproductive parameters. It is unknown whether exposure to PCDF causes similar adverse effects in offspring. The objectives of the study were to investigate the effects of in utero and lactational (IUL) exposure to TCDD and PCDF on subsequent growth, estrous cycles, and ovulation. Additionally a gonadotropin-primed immature rat model was used to investigate possible direct effects on the ovary after IUL exposure to TCDD (2.5 microg/kg) by evaluating 1) ovarian morphometrics and 2) serum estradiol concentrations. Body weights were reduced in animals with IUL exposure to TCDD and PCDF relative to those in controls at 10 days of age (P < 0.05 for each), and this difference was maintained until termination of the experiment at 125-165 days of age (P < 0.05). Exposure to TCDD or PCDF also disrupted regular estrous cycles and inhibited ovulation rate. On Day 23 (before eCG stimulation), ovaries from animals exposed to TCDD contained the same number of primordial, primary, secondary, preantral, and antral follicles as ovaries from control animals. On Day 25 (48 h after eCG stimulation), ovaries from TCDD-exposed rats had significantly fewer large preovulatory follicles when compared with ovaries from controls. The numbers of smaller follicles (both antral and small antral) were not different. Serum estradiol was significantly lower in TCDD-exposed animals 48 h after eCG stimulation.

Abstract  The arylhydrocarbon receptor nuclear translocator (ARNT) is a member of the basic helix-loop-helix, PER-ARNT-SIM family of heterodimeric transcription factors, and serves as a dimerization partner for arylhydrocarbon receptor (AHR) and hypoxia-inducible factor-1alpha. To assess the function of ARNT in T cells, we disrupted the Arnt gene specifically in T cells of mice by conditional gene targeting using T cell-specific p56(lck)-Cre (Lck-Cre) transgenic Arnt-floxed mice. Thus generated, T cell-specific Arnt-disrupted mice (Lck-Cre;Arnt(flox/Delta) transgenic mice) exhibited complete loss of the expression of ARNT protein only in T cells, and were viable and appeared normal. The Arnt-disrupted T cells in the thymus were phenotypically and histologically normal. The Arnt-deficient T cells in the spleen were capable of responding to TCR stimulation in vitro. However, unlike normal mice in which exposure to the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AHR ligand, resulted in thymic involution, the thymus of Lck-Cre;Arnt(flox/Delta) mice were resistant to TCDD treatment in vivo. In contrast, benzo(a)pyrene, another AHR ligand, still caused thymic involution in Lck-Cre;Arnt(flox/Delta) mice. Finally, fetal thymus organ culture using Lck-Cre;Arnt(flox/Delta) and K5-Cre;Arnt(flox/Delta) (epithelial cell-specific Arnt-disrupted mice) showed that thymocytes rather than thymic epithelial cells are predominantly responsible for TCDD-induced thymic atrophy. Our results indicate that ARNT in T lineage cells is essential for TCDD-mediated thymic involution.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. RRM RESEARCH ARTICLE HUMAN POLLUTION TOXICOLOGY ENVIRONMENTAL POLLUTION POLYCHLORINATED BIPHENYLS POLLUTANT TOXIN LACTATIONAL EXPOSURE PERINATAL EXPOSURE PCBS POLYCHLORINATED DIBENZO-P-DIOXINS PCDDS POLYCHLORINATED DIBENZOFURANS PCDFS NEURODEVELOPMENTAL INDICES IMMUNOLOGICAL INDICES ENDOCRINOLOGICAL INDICES REPRODUCTIVE INDICES EPIDEMIOLOGY PCB EXPOSURE DIOXIN EXPOSURE MICHIGAN NORTH CAROLINA USA PALEARCTIC REGION NETHERLANDS DENMARK GERMANY EUROPE FAROE ISLANDS NORTH ATLANTIC YUCHENG TAIWAN

Abstract  Intake fractions (iFs) for emissions to air, water, and soil for 17 PCDDs/DFs and 12 Co-PCBs were calculated with a level III multimedia model and a food-chain exposure model in succession. The two integrated models were tested by comparing the predicted and measured concentrations in the environment and by comparing intakes through food. Measurement-based iFs were also calculated and compared with the model-based iFs. The air concentrations predicted by the fate model were close to the median of the observed concentrations, whereas the predicted soil and water concentrations were one-third to one-tenth the observed concentrations. This difference was large in case of PCDDs and Co-PCBs, which was explained by the past pollution such as commercial PCB products and PCDD impurities in chloronitrofen (CNP) and pentachlorophenol (PCP). For fish, the predicted and observed exposures agreed well each other. For meat and milk, the predicted exposures were about 10 times the observed exposures for PCDDs/DFs, whereas the predicted and observed values agreed well for Co-PCBs. When the model was modified to consider feeding of fish meal to livestock and geographic bias in feed-grass production, the predicted congener profile was comparable to the measured profile. The comparison also suggested that chickens should be modeled separately from other terrestrial livestock. The model-based iFs for air emission of OCDD and 2378-TCDD were 0.001% and 0.1%, respectively. The iFs of most Co-PCBs were higher than those of PCDDs/DFs. These iF differences suggest the importance of the fate factor in assessing emissions of the 29 congeners.

Abstract  The present study has compared the neurobehavioral effects of two structurally different PCB congeners or their combination in rats. Time-mated Long-Evans rats received daily injections of the coplanar PCB 77 (3,4 3',4'-TCB: 0.5 or 1.5 mg/kg), the di-ortho-chlorinated PCB 47 (2,4,2',4'-TCB: 1.5 mg/kg) or a congener mixture (0.5 mg/kg PCB 77 + 1.0 mg/kg PCB 47) from day 7 to 18 of gestation. The PCB exposure levels in brain and perirenal fat of dams and offspring were determined by GC/ECD on gestational day 19 (GD 19), postnatal day 21 (PND 21), and PND 45. PCB 77 was accumulated to a smaller degree than PCB 47. On GD 19, PCB 77 was found to a greater extent in the brains of the offspring than in the brains of the dams, whereas the level of PCB 47 was almost the same in dams and offspring. The testing of open-field behavior in male rats on PND 18 and PND 70 revealed an altered distribution of activity with enhanced activity in the inner zone in PCB 77-treated rats compared to all other groups, while the overall activity was not changed. Distance traveled and rearing behavior on PND 340 were elevated relative to controls in all PCB-treated groups, indicating age-related effects of maternal exposure. A step-down passive avoidance task revealed decreased latencies in the PCB 77 and combined exposure groups on PND 80. Only PCB 77-treated animals showed increased latencies on PND 100 on the haloperidol-induced catalepsy test. These results indicate long-term effects of maternal exposure to PCB 77 on emotional and motor functions. At the dose levels used in the present experiments, the two congeners given in combination did not cause additive or synergistic effects. Instead, concurrent exposure to PCB 47 seemed to counteract PCB 77-induced changes in the pattern of activity.

Abstract  There are large inter- and intraspecies differences in susceptibility to dioxin-induced toxicities. A critical question in risk assessment of dioxin and related compounds is whether humans are sensitive or resistant to their toxicities. The diverse responses of mammals to dioxin are strongly influenced by functional polymorphisms of the arylhydrocarbon receptor (AHR). To characterize responses mediated by the human AHR (hAHR), we generated a mouse possessing hAHR instead of mouse AHR. Responses of these mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene were compared with the responses of naturally sensitive (C57BL6J) and resistant (DBA2) mice. Mice homozygous for hAHR exhibited weaker induction of AHR target genes such as cyp1a1 and cyp1a2 than did C57BL6J (Ahr(b-1/b-1)) mice. DBA2 (Ahr(d/d)) mice were less responsive to induction of cyp genes than C57BL6J mice. hAHR and DBA2 AHR exhibit similar ligand-binding affinities and homozygous hAHR and Ahr(d/d) mice displayed comparable induction of AHR target genes by 3-methylcholanthrene. However, when TCDD was administered, a greatly diminished response was observed in homozygous hAHR mice compared with Ahr(d/d) mice, indicating that hAHR expressed in mice is functionally less responsive to TCDD than DBA2 AHR. After maternal exposure to TCDD, homozygous hAHR fetuses developed embryonic hydronephrosis, but not cleft palate, whereas fetuses possessing Ahr(b-1) or Ahr(d) developed both anomalies. These results suggest that hAHR may define the specificity of the responses to various AHR ligands. Thus, the hAHR knock-in mouse is a humanized model mouse that may better predict the biological effects of bioaccumulative environmental toxicants like TCDD in humans.

Abstract  Effects of postnatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated diberuofurans (PCDFs) and coplanar polychlorinated biphenyls (Co-PCBs) on lymphocyte subpopulations were investigated in the peripheral blood of 36 breast-fed Japanese babies. As a result, estimated total intakes of these chemicals in toxic equivalent quantity (TEQ) converted into 2,3,7,8- tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) equivalents from the breast milk positively and negatively correlated with the respective percentages of CD4+ and CDS+ lymphocytes in the blood of breast-fed babies. Consequently, the ratios of CD4+ to CDS+ T cells showed significant increasing tendency with the estimated total TEQ intakes. Therefore, our study suggests that exposure to background levels of the highly toxic organochlorine compounds through the breast milk influences the human neonatal immune system.

Abstract  OBJECTIVE: We investigated the association between body mass index (BMI) standard deviation score (SDS) and prenatal exposure to hexachlorobenzene, dichlorodiphenyldichloroethylene (DDE), dioxin-like compounds, and polychlorinated biphenyls (PCBs). METHODS: In this prospective birth cohort study, we assessed a random sample of mother-infant pairs (n = 138) living in Flanders, Belgium, with follow-up until the children were 3 years of age. We measured body mass index as standard deviation scores (BMI SDS) of children 1-3 years of age as well as pollutants measured in cord blood. RESULTS: DDE correlated with BMI SDS, with effect modification by maternal smoking and the child's age. At 1 year, children of smoking mothers had higher BMI SDS than did children of nonsmoking mothers. At 3 years, this difference was reduced because of the faster rate of decline in BMI SDS in the former group. This relationship held except for children with high levels of DDE. DDE had a small effect on BMI SDS at 3 years of age in children of nonsmoking mothers (difference in BMI SDS for DDE concentrations between the 90th and 10th percentiles = 0.13). On the other hand, smoking enhanced the relation between DDE and BMI SDS at 3 years (difference in BMI SDS for DDE concentrations between the 90th and 10th percentiles = 0.76). Increasing concentrations of PCBs were associated with higher BMI SDS values at all ages (parameter estimate = 0.003 +/- 0.001; p = 0.03). CONCLUSION: In this study we demonstrated that intrauterine exposure to DDE and PCBs is associated with BMI during early childhood. Future studies are warranted to confirm our findings and to assess possible mechanisms by which these pollutants could alter energy metabolism.

Abstract  Toxic equivalency factor (TEF) has been proposed to estimate the risk of polychlorinated biphenyl (PCB) congeners. However, ortho chlorine substitution in the two phenyl rings gives each PCB its own pattern of toxicity which is different from the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin. The present study evaluated the effect of prenatal and postnatal exposure to a low dose of the mono-ortho pentachlorobiphenyl PCB 118 on thyroid hormone concentrations and EROD activity in rats. Moreover, the tissue distribution of PCB 118 following one oral dose was evaluated. Sprague-Dawley rats were treated by gavage on GD 6 with 375 microg of PCB 118/kg b.w. Decreases in thyroxine and TSH levels were observed in dams at the end of lactation. Perinatal exposure to a low dose of PCB 118 permanently disrupted the hypothalamo-pituitary-thyroid (HPT) axis leading to a significant increase in thyroxine levels in offspring, as a 'thyroid resistance syndrome'. It is noteworthy that no changes in hepatic EROD activity were detected in dams at the end of lactation, even in the presence of high amounts of PCB in liver. Based on hepatic EROD activity (as a biomarker for aryl hydrocarbon receptor (AhR) induction), the mechanism of thyroid homeostasis disruption seems to be AhR-independent. Additionally, the 'thyroid resistance syndrome' observed in our study indicates the need for further detailed investigations on the HPT axis. We conclude that not only TEF, but also AhR-independent responses should be taken into account for risk assessment of mono-ortho PCB congeners.

Abstract  The generic term "dioxin" covers more than 400 chemicals of which less than 30 prove to be toxic. Such compounds are involved in environmental pollutions and in food contaminations. Some selected dioxins have also been used as a non-lethal chemical weapon. The assessment of the impact on health needs a precise toxicological identification. Without that basic assessment, a discrepancy may appear between the real risk linked to the exposure and the concerns and fear generated in the population, particularly because in animals the toxic concentrations of dioxins can interfere with some hormonal systems, alter immunity, induce chloracne, and participate in the development of sarcomas, lymphomas and some carcinomas. They may be responsible for some birth defects.