Prenatal exposure to polychlorinated biphenyls and dioxins is associated with increased risk of wheeze and infections in infants
Food and Chemical Toxicology(2011)
摘要
The birth cohort BraMat ( n = 205; a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health) was established to study whether prenatal exposure to toxicants from the maternal diet affects immunological health outcomes in children. We here report on the environmental pollutants polychlorinated biphenyls (PCBs) and dioxins, as well as acrylamide generated in food during heat treatment. The frequency of common infections, eczema or itchiness, and periods of more than 10 days of dry cough, chest tightness or wheeze (called wheeze) in the children during the first year of life was assessed by questionnaire data ( n = 195). Prenatal dietary exposure to the toxicants was estimated using a validated food frequency questionnaire from MoBa. Prenatal exposure to PCBs and dioxins was found to be associated with increased risk of wheeze and exanthema subitum, and also with increased frequency of upper respiratory tract infections. We found no associations between prenatal exposure to acrylamide and the health outcomes investigated. Our results suggest that prenatal dietary exposure to dioxins and PCBs may increase the risk of wheeze and infectious diseases during the first year of life. Abbreviations BMI body mass index Bw body weight dl-PCBs dioxin-like PCBs FFQ food frequency questionnaire MBRN the Medical Birth Registry of Norway MoBa the Norwegian Mother and Child Cohort Study ndl-PCBs non-dioxin-like PCBs PCBs polychlorinated biphenyls PCDDs/PCDFs polychlorinated dibenzo-p-dioxins/dibenzofurans Keywords Polychlorinated biphenyls Dioxins Acrylamide Prenatal exposure Wheeze Infections 1 Introduction The food we eat contains small amounts of substances that can have harmful effects on our immune system. Adverse effects on the immune system may influence the development of immune-related diseases like allergy, asthma, and autoimmune conditions, or increase susceptibility to infectious diseases. In our study, we addressed the dietary toxicants organochlorines (polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDDs/PCDFs; commonly called dioxins)) and acrylamide. PCBs and dioxins are environmental pollutants for which food is the main source of human exposure (constituting more than 90%) ( Ross, 2004; Charnley and Doull, 2005; Domingo and Bocio, 2007; Bergkvist et al., 2008 ). These toxicants are lipophilic and resistant to degradation processes, and therefore accumulate in the food chain. Food is also the main source of human exposure to acrylamide for the general non-smoking population ( Carere, 2006; Parzefall, 2008; Hogervorst et al., 2010 ). Acrylamide can be generated in certain foods, particularly plant-based foods that are rich in carbohydrates, during heat treatment at temperatures above 120 °C ( Mottram et al., 2002; Stadler et al., 2002 ). Studies have shown that PCBs and dioxins, as well as acrylamide, cross the placenta and reach the foetus ( Covaci et al., 2002; Sorgel et al., 2002; Schettgen et al., 2004; Annola et al., 2008; Park et al., 2008 ). Foetal exposure to immunotoxicants is of concern because the immune system develops extensively during the foetal stage and the foetus may therefore be especially vulnerable to toxicant exposure ( West, 2002; Holsapple et al., 2004; van Loveren and Piersma, 2004 ). Even though the levels of exposure to PCBs and dioxins are decreasing worldwide ( Dallaire et al., 2003; Noakes et al., 2006; Polder et al., 2008; Llobet et al., 2008 ), effects of PCB and dioxin exposure on immunological parameters in humans are reported. With regard to prenatal exposure, associations between high levels of PCBs and increased risk of acute infections early in life have been observed in an Inuit population in Canada ( Dallaire et al., 2004, 2006 ). In the Faroe Islands, prenatal exposure to high levels of PCBs was found to be inversely associated with a history of atopic dermatitis and antibody responses upon vaccination ( Heilmann et al., 2006; Grandjean et al., 2010 ). Even in populations that are assumed to be less exposed than those in the above mentioned studies, immunotoxic effects of prenatal exposure to PCBs and dioxins have been observed ( Weisglas-Kuperus et al., 2000, 2004; ten Tusscher et al., 2003; Glynn et al., 2008 ). However, only few human studies have investigated immunotoxic effects of prenatal exposure to PCBs and dioxins with exposure levels more likely to be representative for the general population. Information on immunotoxicity of acrylamide is scarce, while carcinogenic, genotoxic, neurotoxic, and reproductive toxic properties of acrylamide have been reported ( Carere, 2006; Parzefall, 2008; Hogervorst et al., 2010 ). Zaidi et al. (1994) however, reported immunosuppressive effects of acrylamide exposure in rats. To our knowledge no studies investigating possible immunotoxic effects in humans or animals of prenatal exposure to acrylamide have been published. The present study is part of the EU-funded project NewGeneris with the overall aim to investigate whether maternal exposure to dietary toxicants results in in utero exposure and molecular events in the unborn child, leading to increased risk of cancer and immune disorders in childhood ( Merlo et al., 2009 ). A birth cohort (BraMat) was established which included children born in the Oslo area in Norway. The aim of the present study was to investigate the effect of exposure to PCBs and dioxins, and acrylamide from the maternal diet during pregnancy on immunological health outcomes in infants (0–12 months of age). Health outcomes investigated were the frequency of common infections, eczema or itchiness, and periods of more than 10 days of dry cough, chest tightness or wheeze during the child’s first year of life. BraMat is assumed to be representative for the general population with regard to exposure levels of PCBs and dioxins, as well as acrylamide. Previous studies on the effect of pre- and postnatal exposure to PCBs and dioxins have used measurements in biological samples such as cord blood and breast milk, which reflect the body burden of these toxicants. For counselling the pregnant women with regard to their diet, it is important to get an indication also of the effect on the child of PCB and dioxin intake via food during pregnancy since little can be changed over a few months with regard to the body burden. In the present study, exposure to PCBs and dioxins, and acrylamide through food was investigated using an extensive and well validated food frequency questionnaire (FFQ) ( Meltzer et al., 2008; Brantsaeter et al., 2008a ), giving an estimate of the average maternal daily intake of the toxicants during the first four months of pregnancy. 2 Methods 2.1 Study population Between April 2007 and March 2008, invitations to participate in the birth cohort BraMat were sent by regular mail to all pregnant women already attending the Norwegian Mother and Child Cohort Study (MoBa) and who were scheduled to give birth at Oslo University Hospital Ullevål and Akershus University Hospital. MoBa is a prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health, where participants were recruited from all over Norway from 1999–2008 ( Magnus et al., 2006 ). Invitations to the BraMat-study were sent in week 37 of gestation, thus only infants that had experienced a full term pregnancy (37th – 42nd week of gestation) were included. There were no plurality births. Exclusion criteria in the BraMat cohort were autoimmune diseases of the mother, and use of steroids, anti-inflammatory, or epileptic drugs during pregnancy. The study was approved by the Norwegian Regional Committee for Medical and Health Research Ethics and the Data Inspectorate. All mothers gave their written informed consent. 2.2 Exposure assessments Maternal exposure to the dietary toxicants polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDDs/PCDFs or dioxins), and acrylamide was estimated from a validated food frequency questionnaire (FFQ) used in MoBa. Description and validation of the FFQ are described elsewhere ( Meltzer et al., 2008; Brantsaeter et al., 2008a ). The FFQ covers the dietary intake of the participants during the first four months of pregnancy. The questions are adapted to Norwegian food habits and include also rarely eaten food items with known high levels of PCBs and dioxins, and acrylamide. Primarily, concentrations from analyses of Norwegian foods were used in the estimation calculations. Humans are exposed to mixtures of congeners of PCBs and dioxins through their diet. We chose to use mixtures of congeners in our analyses since the congeners may be highly correlated and hence not possible to discriminate between the effects of the different congeners. PCBs and dioxins can be divided into two groups according to their toxicological properties: (1) dioxins and dioxin-like PCBs (dl-PCBs) and (2) non-dioxin-like PCBs (ndl-PCBs). Similar toxicological properties of dioxins and dl-PCBs allow the combined exposure to be expressed as toxic equivalents (TEQ) ( van den Berg et al., 1998, 2006 ). The most toxic congeners were included in the TEQ calculations: all 17 of the 2,3,7,8-substituted PCDD/PCDFs; non-ortho-substituted PCBs: PCB-77, 81, 126 and 169; mono-ortho-substituted PCBs: PCB-105, 114, 118, 123, 156, 157, 167 and 189. To investigate effects of ndl-PCBs, the sum of exposure to PCB-28, 52, 101, 138, 153 and 180 (PCB 6 ) was used. These congeners account for approximately 50% of the ndl-PCBs in food ( EFSA, 2005 ). The method for estimation of exposure to acrylamide, PCBs and dioxins has been described in Brantsaeter et al. (2008b) and Kvalem et al. (2009) , respectively. In these studies, the estimated values of PCBs and dioxins were found to be correlated with blood concentrations, and estimated values of acrylamide with concentrations of acrylamide metabolites in urine. The exposure was expressed relative to the mother’s self-reported body weight (bw) before pregnancy, thus the exposure to dioxins and dl-PCBs was expressed as pg TEQ/kg bw/day, exposure to ndl-PCBs as ng/kg bw/day, and acrylamide as μg/kg bw/day. 2.3 Health outcomes, potential predictor and confounding variables 2.3.1 Health outcomes When the children in the BraMat cohort were one year of age, a questionnaire was sent to the mothers. The mothers had the choice of filling in the questionnaire and returning it by regular mail or to answer the questionnaire by telephone interview. The questionnaire covered topics on the child’s infectious diseases, allergy, asthma, and other chronic diseases, and the use of medications. Concerning infectious diseases, the mothers were asked if the child had experienced the following diseases/complaints at 0–12 months of age, and how many episodes: colds and other upper respiratory tract infections, otitis media, pneumonia, gastric flu with vomit or diarrhoea, and urinary tract infection. The mothers were also asked if the child had experienced any common childhood infections, e.g. chicken pox and exanthema subitum (roseola infantum). Concerning allergy, asthma, and other chronic diseases, the mothers were asked: “Has the child been diagnosed with asthma or asthma bronchitis by a doctor? Has the child had periods of more than 10 days of dry cough, chest tightness, or wheeze (hereafter called wheeze)? Has the child had eczema or itchiness (in the face or at joints such as groin, popliteal fossa, ankle, elbow, and wrist)? Has the child been diagnosed with allergy by a doctor? Has the child any other chronic diseases?” 2.3.2 Potential predictor variables The exposure levels of the dietary toxicants were categorized using the 80th percentile to compare the highest exposed participants with the remaining participants (⩾80th percentile and <80th percentile respectively). The exposure variables were positively skewed, and by using the 80th percentile, the participants that constitute the tail of the exposure distribution was defined as the highest exposed participants. If no statistically significant associations were found when the categorized exposure variables were used, also the continuous exposure variables were examined. For eczema, exposure levels to dioxins and dl-PCBs, and ndl-PCBs were divided into three categories using the tertiles (33rd and 66th percentiles), due to nonlinear associations. The reference category was always the lowest exposure category. 2.4 Potential confounding variables Potential confounding variables were extracted from MoBa questionnaires filled in by the mothers during pregnancy (∼15th and 30th week of gestation) and about six months after birth. The present study was based on the latest version (version 5) of the quality-assured data files. Information about the birth was extracted from the Medical Birth Registry of Norway (MBRN). Potential confounding variables included in the analyses were mother’s previous breast-feeding, parity, maternal history of atopy, maternal age, maternal smoking, maternal passive smoking, maternal education, maternal BMI, child’s gender, birth season, type of delivery, breast-feeding of the child at six months, Apgar score after 1 min, and day-care attendance at 12 months. Categories of the variables used in the analyses are shown in Table 1 . Birth weight and gestational age were not included in the analyses since only full term pregnancies were included in our study and only two infants had lower birth weight than 2.500 g (2200–2500). 2.5 Statistical analyses Logistic regression analyses were applied to assess the influence of potential predictor variables and adjust for confounding variables on the different binary health outcomes for the children. The criterion for inclusion of potential confounding variables in the multivariate regression analyses was p < 0.250 in bivariate logistic regression analysis. Manual backward deletion method was used starting with all included variables in the model. At each deletion step, the variable that was the least significant in the multivariate model was manually removed, but only when it did not result in changes >15% in the effect estimate of the exposure variable. Variables were removed one by one until only statistically significant ( p < 0.05) variables remained in the model. Hosmer–Lemeshow test, Cooks’D, and residuals were used to investigate the robustness of the multivariate logistic regression models. For the outcome variable “number of upper respiratory tract infections”, linear regression analyses were applied since the residuals were approximately normally distributed. The inclusion criterion for potential predictor variables in the multivariate regression analyses was the same as described above. Cooks’D, Leverage values, and residuals were used to investigate the robustness of the multivariate linear regression models. Because of categorical and non-normally distributed variables, Kendall’s rank correlation coefficient was used to investigate the correlation between two variables. Results were considered statistically significant at p < 0.05. The statistical analyses were performed using the statistical software PASW Statistics 17 (SPSS Inc., Chicago, IL, USA). 3 Results Of all the invited mothers, 38.5% chose to participate in MoBa, and of these participants, about 25% of the mothers chose to participate in the present BraMat study. Questionnaires about the child’s health from 0–12 months of age were received from 195 of 205 (95%) mothers. The questionnaire was filled in and returned by regular mail by 46.2% of the mothers and 53.8% answered the questionnaire by telephone interview. Some of the 195 questionnaires were not complete. This was especially true for the reporting of number of episodes with colds and other upper respiratory tract infections (seven missing). Demographics and the frequencies of the health outcomes of the study population ( n = 195) are shown in Table 1 , and the estimated dietary intake of the mothers of dioxins and dl-PCBs, ndl-PCBs, and acrylamide is presented in Table 2 . As expected in infants and in a small study population, the frequency of the health outcomes pneumonia, urinary tract infection, doctor diagnosed allergy and asthma, and other chronic diseases were low. Therefore, statistical analyses were not performed. For the remaining health outcomes, the results of bivariate logistic or linear regression analyses are presented in Table 3 . The exposure levels of dioxins and dl-PCBs, and ndl-PCBs were highly correlated (τ b = 0.81, p < 0.001), therefore separate statistical multivariate analyses were performed for these dietary toxicants. In the multivariate regression analyses, prenatal dietary exposure to dioxins and dl-PCBs, and ndl-PCBs was found to increase the risk of wheeze ( Table 4 ). The exposure levels of the dietary toxicants were the only variables associated with wheeze, and were the only variables remaining in the final models. Adjusted for maternal education, prenatal exposure to dioxins and dl-PCBs, and ndl-PCBs was associated with increased number of colds and other upper respiratory tract infections. However, for dioxins and dl-PCBs, significant association was observed only when the continuous exposure variable of the dietary toxicants was used. Prenatal exposure to dioxins and dl-PCBs, and ndl-PCBs also increased the risk of the common childhood infection exanthema subitum when the continuous exposure variables of the dietary toxicants were used. The exposure variables were the only variables remaining in the final models. Increased prenatal exposure to dioxins and dl-PCBs, and ndl-PCBs was also found to lower the risk of eczema or itchiness in bivariate logistic regression analyses when the levels of exposure to dietary toxicants were categorized using the tertiles ( Table 3 ). However, when adjusted for maternal BMI in the final models, the associations were not significant (ndl-PCB: OR (95% CI) p -value; 1st vs 2nd tertile: 0.45 (0.18–1.14) 0.091; 1st vs 3rd tertile: 0.83 (0.36–1.91) 0.668; dioxins and dl-PCBs: 1st vs 2nd tertile: 0.49 (0.20–1.22) 0.127; 1st vs 3rd tertile: 0.76 (0.32–1.78) 0.521). No significant associations between health outcomes and acrylamide exposure were found. 4 Discussion In the present study, dietary exposure to PCBs and dioxins from the maternal diet during pregnancy was found to be associated with immunological health outcomes in the children during the first year of life. No associations between prenatal dietary exposure to acrylamide and the investigated health outcomes were observed. Prenatal dietary exposure to dioxins and PCBs was associated with increased risk of wheeze during the first year of life. Wheeze may be divided into distinct phenotypes, and the most common are transient infantile wheeze, viral-associated wheeze, and atopic wheeze ( Stein and Martinez, 2004; Sly et al., 2008 ). The two first are the most common phenotypes in the first years of life. In the present study, we cannot differentiate between the three wheezing phenotypes. However, when wheeze was combined with the number of upper respiratory tract infections (<7 or ⩾7 episodes of infections) during the first year of life, we observed a significantly stronger association between prenatal exposure to PCBs and dioxins and wheeze along with seven or more episodes of infections compared to wheeze along with less than seven episodes (results not shown). Although we do not want to conclude based on these findings, since the power of the analysis is low, our results suggest that the observed association between prenatal dietary exposure to PCBs and dioxins and wheeze can be due to respiratory infections. This finding is in accordance with the study of Weisglas-Kuperus et al. (2000) reporting dioxin exposure, as measured in breast milk, to be associated with a higher occurrence of coughing, chest congestion and phlegm lasting for 10 days or more in 42 months old children. On the other hand, they also found that prenatal PCB exposure was associated with less shortness of breath with wheeze in both 42 months old children and at school age ( Weisglas-Kuperus et al., 2000, 2004 ). The children investigated in our study are younger than in the above mentioned studies, and for the majority of infant wheezers, most wheeze and wheeze-related symptoms resolve between the ages of 3 and 5 years ( Stein and Martinez, 2004; Sly et al., 2008 ). Therefore, to investigate whether there is an association between prenatal dietary exposure to PCBs and dioxins and the development of persistent wheeze and asthma, the children in our study will be followed into later childhood. In the present study, prenatal dietary exposure to PCBs and dioxins was associated with increased number of colds and other upper respiratory tract infections as well as increased risk of the common childhood infection exanthema subitum. We also observed a similar tendency for otitis media ( Table 3 ). These results indicate that prenatal exposure to dietary PCBs and dioxins increases the risk of infectious diseases. In the study of Glynn et al. (2008) where prenatal exposure to PCBs of Swedish children was investigated, divergent results were found for different PCB congeners and the risk of respiratory infections. In other studies, pre- and postnatal exposure to PCBs was associated with a higher frequency of respiratory infections; especially lower respiratory tract infections and otitis media ( Weisglas-Kuperus et al., 2000, 2004; Dallaire et al., 2004, 2006 ). In addition, Weisglas-Kuperus et al. (2000) reported exposure to PCBs to increase the risk of the common childhood disease chicken pox before pre-school age. Thus, our finding of greater susceptibility to infectious diseases due to prenatal dietary exposure to PCBs and dioxins is in accordance with the published literature. The levels of dioxins and dl-PCBs, and ndl-PCBs were highly correlated ( τ b = 0.81, p < 0.001). Thus, we could not discriminate whether it was the dioxins and dl-PCBs, or ndl-PCBs, or both groups that were associated with the health outcomes. However, our finding of increased risk of infectious diseases associated with prenatal dietary exposure to PCBs and dioxins is in accordance with the proposed immunosuppressive effects of dioxins and dl-PCBs. Studies have found that dioxins and dl-PCBs, which are potent ligands of the aryl hydrocarbon receptor (AhR), may expand the population of T regulatory cells, possibly resulting in suppressed immune responses ( Funatake et al., 2005; Quintana et al., 2008; Ho and Steinman, 2008; Kerkvliet et al., 2009 ). In accordance with this notion, we observed a tendency of exposure to dioxins and dl-PCBs, and ndl-PCBs to lower the risk of eczema and itchiness in the face or at joints such as the groin, popliteal fossa, ankle, elbow, and wrist, which are typical for atopic eczema. The study of Grandjean et al. (2010) also reported a negative association between prenatal PCB exposure and atopic eczema. An unifying mechanistic explanation for our findings therefore is Ahr-mediated immune suppression by PCBs and dioxins, resulting in more infections and infection-dependent wheeze, and less inflammatory diseases like atopic eczema. However, in the above mentioned studies regarding the effect mechanism of dioxins and dl-PCBs, prenatal exposure was not investigated, and the immune system of the foetus, children and adults may respond differently to chemical exposures. We did not find any associations between prenatal dietary exposure to acrylamide and the health outcomes investigated. Although the power is too low to conclude on negative findings, our findings are supported by the published literature, which does suggest carcinogenic, genotoxic, neurotoxic, and reproductive toxic, but not immunotoxic, properties of acrylamide ( Carere, 2006; Parzefall, 2008; Hogervorst et al., 2010 ). To our knowledge, only Zaidi et al. (1994) have reported immunosuppressive effects of acrylamide exposure in vivo in an animal study, but prenatal exposure was not investigated. Long-term follow-up of children should be performed to further study whether prenatal exposure to acrylamide affects the immunological health outcomes in later child- and adulthood. It is a challenge to distinguish between prenatal and postnatal exposure to dietary toxicants in epidemiological studies. In the present study, prenatal exposure was investigated. However, the PCBs and dioxins are transferred to breast milk ( Sorgel et al., 2002; Ayotte et al., 2003 ), thus children will also be exposed to PCBs and dioxins postnatally through breast feeding. Therefore, we cannot identify the existence of a critical time window for exposure to PCBs and dioxins. The strengths of the present study are that the food frequency questionnaire used is well validated, and the extensive information about the children and mothers available from MoBa and MBRN. To our knowledge, no other studies have used a similar food frequency questionnaire to investigate whether prenatal dietary intake of PCBs and dioxins, as well as acrylamide, affects the immunological health outcomes in children. The study may have a selection bias due to the 38.5% participation rate of the invited mothers in MoBa, and of the MoBa participants, about 25% of the invited mothers chose to participate in the BraMat study. The potential selection bias in MoBa was recently evaluated by Nilsen et al. (2009) . No statistically relative differences in association measures were found between participants and all women giving birth in Norway regarding the eight exposure-outcome associations evaluated ( Nilsen et al., 2009 ). Thus the observed associations between predictor variables and health outcomes are regarded as valid. The mothers had the choice of returning the questionnaire by regular mail or to answer the questionnaire by telephone interview. The interviewers were instructed to ask the questions as written in the questionnaires and not to discuss the answers. No statistically significant differences were found with regard to frequency of health outcomes when comparing written questionnaires and telephone interviews (results not shown). In conclusion, no associations were found between prenatal dietary exposure to acrylamide and the immunological health outcomes investigated in children in Norway during the first year of life. However, our results suggest that prenatal dietary exposure to PCBs and dioxins may increase the risk of wheeze and infectious diseases. Whereas little can be changed with regard to the body burden of PCBs and dioxins during a few months, our study suggests that dietary intervention to reduce PCB and dioxin intake during pregnancy may provide a health benefit for the child. To further explore whether there is an association between prenatal dietary exposure to PCBs and dioxins, and the development of asthma and allergic diseases, a follow-up into later childhood is planned. Conflict of Interest The authors declare that there are no conflicts of interest. Acknowledgements We thank children and parents for participating in the BraMat birth cohort. This work was supported by the EU Integrated Project NewGeneris, 6th Framework Programme, Priority 5: Food Quality and Safety (FOOD-CT-2005-016320). NewGeneris is the acronym of the project “Newborns and Genotoxic exposure risks”, http://www.newgeneris.org . The Norwegian Institute of Public Health also contributed to the funding of the study. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no. 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BMI,Bw,dl-PCBs,FFQ,MBRN,MoBa,ndl-PCBs,PCBs,PCDDs/PCDFs
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