Prenatal exposure to TCDD and atopic conditions in the Seveso second generation: a prospective cohort study.
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ABSTRACT: Background
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant that can bioaccumulate in humans, cross the placenta, and cause immunological effects in children, including altering their risk of developing allergies. On July 10, 1976, a chemical explosion in Seveso, Italy, exposed nearby residents to a high amount of TCDD. In 1996, the Seveso Women's Health Study (SWHS) was established to study the effects of TCDD on women's health. Using data from the Seveso Second Generation Health Study, we aim to examine the effect of prenatal exposure to TCDD on the risk of atopic conditions in SWHS children born after the explosion.Methods
Individual-level TCDD was measured in maternal serum collected soon after the accident. In 2014, we initiated the Seveso Second Generation Health Study to follow-up the children of the SWHS cohort who were born after the explosion or who were exposed in utero to TCDD. We enrolled 677 children, and cases of atopic conditions, including eczema, asthma, and hay fever, were identified by self-report during personal interviews with the mothers and children. Log-binomial and Poisson regressions were used to determine the association between prenatal TCDD and atopic conditions.Results
A 10-fold increase in 1976 maternal serum TCDD (log10TCDD) was not significantly associated with asthma (adjusted relative risk (RR) = 0.93; 95% CI: 0.61, 1.40) or hay fever (adjusted RR = 0.99; 95% CI: 0.76, 1.27), but was significantly inversely associated with eczema (adjusted RR = 0.63; 95% CI: 0.40, 0.99). Maternal TCDD estimated at pregnancy was not significantly associated with eczema, asthma, or hay fever. There was no strong evidence of effect modification by child sex.Conclusions
Our results suggest that maternal serum TCDD near the time of explosion is associated with lower risk of eczema, which supports other evidence pointing to the dysregulated immune effects of TCDD.
SUBMITTER: Ye M
PROVIDER: S-EPMC5827999 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundExposure to endocrine disrupting compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during susceptible developmental windows may alter risk of metabolic disease later in life. Animal studies of in utero and lactational TCDD exposure report associations with alterations in insulin sensitivity and energy homeostasis, but epidemiologic evidence is limited. We examined the relationship of prenatal TCDD exposure with markers of glucose homeostasis in the Seveso Second Generation study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 explosion in Seveso, Italy.MethodsWe included 426 children who were 18?years or older with complete follow-up data including a fasting blood draw. Insulin and glucose were measured and the updated homoeostatic model assessment was used to estimate insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B). Prenatal TCDD exposure was defined in two ways, as initial maternal serum TCDD concentration and TCDD estimated at pregnancy.ResultsThe children (222 female, 204 male) averaged 28.6 (±6.0) years. We found a 10-fold increase in TCDD estimated at pregnancy was inversely associated with insulin (adj-??=?-1.24 ?IU/mL, 95% confidence interval (CI): -2.38, -0.09) and HOMA2-B (adj-??=?-10.2% decrease, 95% CI: -17.8, -1.9) among daughters, but not sons (insulin: adj-??=?0.57 ?IU/mL, 95% CI: -0.84, 1.98, P for interaction?=?0.04; and HOMA2-B: adj-??=?0.8% increase, 95% CI -10.7, 13.9, P for interaction?=?0.11). Similar effect modification was observed for TCDD estimated at pregnancy and HOMA2-IR (P for interaction?=?0.13). The models for initial maternal serum TCDD showed similar effect modification by child sex. The observed associations in daughters showed evidence of mediation by body mass index, which we have previously found to be associated with prenatal TCDD exposure in female offspring.ConclusionThese results suggest prenatal exposure to TCDD is associated with lower insulin resistance and beta compensation in female offspring, and show evidence of mediation by body mass index.
| S-EPMC6904529 | biostudies-literature
Project description:BackgroundIn animal studies, perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters thyroid homoeostasis and thyroid hormone concentrations; epidemiologic evidence is limited.ObjectivesWe aimed to determine the association of prenatal exposure to TCDD with thyroid hormone concentrations in the Seveso Second Generation Study, a unique cohort of children born to TCDD-exposed women resulting from a 1976 chemical factory explosion in Seveso, Italy.MethodsWe included 570 children (288 female, 282 male) with complete follow-up data, including a fasting blood draw. Serum levels of total and free thyroxine (T4), free triiodothyronine (T3), and thyroid stimulating hormone (TSH) were measured using immunoassays. We defined prenatal TCDD exposure as: 1) maternal initial TCDD concentration measured in serum collected soon after the explosion and 2) maternal TCDD estimated at pregnancy.ResultsCompared to the lowest quartile (Q1), maternal initial serum TCDD was associated with lower free T3 (Q2: adj-β = -0.13, 95%CI -0.26, 0.00; Q3: adj-β = -0.22, 95%CI -0.35, -0.09; Q4: adj-β = -0.14, 95%CI -0.28, 0.00; p-trend = 0.02). In participants with high thyroid antibody status, inverse associations between maternal initial serum TCDD and free T3 were significantly stronger than in participants with normal antibody status (p-interaction = 0.02). We also observed a positive association between maternal initial serum TCDD and TSH concentrations in participants with high thyroid antibody status (Q2: adj-β = 11.4%, 95%CI -25.2, 66.1; Q3: adj-β = 49.0%, 95%CI 3.0, 115.5; Q4: adj-β = 105.5, 95%CI 36.6, 209.2; p-trend < 0.01) but not in those participants with normal antibody status (p-interaction < 0.01). Similar results were found for TCDD estimated at pregnancy.DiscussionOur results suggest prenatal exposure to TCDD, a potent endocrine-disrupting compound, may alter thyroid function later in life. Populations with additional thyroid stress may be particularly susceptible to in utero exposure of thyroid disrupting chemicals.
| S-EPMC7176740 | biostudies-literature
Project description:BackgroundPrenatal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure has been shown to alter sexual differentiation of the brain in animal models, impacting pubertal development, behavior, cortical dominance, and cognition. The effects of early life exposure to dioxin-like compounds on human neurodevelopment, however, are less clear and warrant further investigation.MethodsThe Seveso Women's Health Study (SWHS), initiated in 1996, is a well-characterized cohort of 981 Italian women who lived in proximity to an industrial accident in July 1976 that resulted in one of the highest residential TCDD exposures on record. In 2014-2016, we enrolled offspring born after the accident into the Seveso Second Generation Health Study. Children aged 7-17 years old (n = 161) completed a neuropsychological assessment spanning executive function and reverse learning (Wisconsin Card Sort), non-verbal intelligence (Raven's Progressive Matrices), attention and hyperactivity (Connor's Continuous Performance (CPT), and memory (Rey's Auditory Verbal Learning). We used multivariate regression with robust standard error estimates accounting for clustering of siblings to model the associations between these outcomes and prenatal exposure defined as TCDD measured in maternal serum collected soon after the explosion and estimated to pregnancy.ResultsThe children (82 male, 79 female) averaged 13.1 (±2.9) years of age. Adjusting for covariates, a 10-fold increase in maternal serum TCDD was not adversely associated with reverse learning/set-shifting, memory, attention/impulsivity, or non-verbal intelligence. In sex-stratified models, prenatal TCDD was associated with more non-perseverative errors in boys but not in girls (pint = 0.04). TCDD was also associated with attention deficits on the CPT but only among children with the shortest breastfeeding histories.ConclusionsWhile overall, there were no significant associations, the observed differential neurotoxic sensitivities to TCDD by sex and lactation history may warrant confirmation in future studies.
| S-EPMC6440851 | biostudies-literature
Project description:Background/objectivesIn utero exposure to endocrine-disrupting compounds such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) may alter risk of obesity and related metabolic disease later in life. We examined the relationship of prenatal exposure to TCDD with obesity and metabolic syndrome (MetS) in children born to a unique cohort of TCDD-exposed women resulting from a 1976 explosion in Seveso, Italy.Subjects/methodsIn 2014, nearly 40 years after the explosion, we enrolled 611 post-explosion offspring, 2 to 39 years of age, in the Seveso Second Generation Study. In utero TCDD exposure was defined primarily as TCDD concentration measured in maternal serum collected soon after the explosion and alternately as TCDD estimated at pregnancy. We measured height, weight, waist circumference, body fat, blood pressure, and fasting blood levels of lipids and glucose, which were combined to assess body mass index (BMI) and MetS.ResultsChildren (314 female, 297 male) averaged 23.6 (±6.0) years of age. Among the 431 children ≥18 years, a 10-fold increase in initial maternal TCDD concentration was inversely associated with BMI in daughters (adj-β = -0.99 kg/m2; 95% CI -1.86, -0.12), but not sons (adj-β = 0.41 kg/m2; 95% CI -0.35, 1.18) (p-int = 0.02). A similar relationship was found in the younger children (2-17 years); a 10-fold increase in initial maternal TCDD was inversely associated with BMI z-score (adj-β = -0.59 kg/m2; 95% CI -1.12, -0.06) among daughters, but not sons (adj-β = 0.04 kg/m2; 95% CI -0.34, 0.41) (p-int = 0.03). In contrast, in sons only, initial maternal TCDD was associated with increased risk for MetS (adj-RR = 2.09, 95% CI 1.09, 4.02). Results for TCDD estimated at pregnancy were comparable.ConclusionsThese results suggest prenatal TCDD exposure alters cardiometabolic endpoints in a sex-specific manner. In daughters, in utero TCDD is inversely associated with adiposity measures. In sons, in utero TCDD is associated with increased risk for MetS.
| S-EPMC6639155 | biostudies-literature
Project description:BACKGROUND:Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been reported to suppress immune function. However, previous studies on prenatal exposure to PFASs and allergic disorders in offspring provided inconsistent results. We aimed to examine the association between prenatal exposure to PFASs and childhood atopic dermatitis (AD) in offspring up to 24 months of age. METHODS:A prospective birth cohort study involving 1056 pregnant women was conducted in two hospitals in Shanghai from 2012 to 2015. Prenatal information was collected by an interview with the women and from medical records. Fetal umbilical cord blood was collected at birth. Cord blood plasma PFASs were measured. Children were followed at 6, 12 and 24 months and information on the development of AD was recorded. AD was diagnosed by 2 dermatologists independently based on the questionnaires. Multiple logistic regression was used to compute odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between AD and each PFASs, adjusting for potential confounders. RESULTS:A total of 687 children completed a 2-year follow-up visit and had PFASs measurement. AD was diagnosed in 173 (25.2%) children during the first 24 months. In female children, a log-unit increase in perfluorooctanoic acid (PFOA) was associated with a 2.1-fold increase in AD risk (AOR 2.07, 95% CI 1.13-3.80) after adjusting for potential confounders. The corresponding risk was 2.22 (1.07-4.58) for perfluorononanoic acid (PFNA). The highest PFOA quartile was significantly associated with AD (2.52, 1.12-5.68) compared with the lowest quartile. The highest quartile of PFNA, perfluorodecanoic acid (PFDA) and perfluorohexane sulfonic acid (PFHxS) were associated with AD with AOR (95% CI) being 2.14 (0.97-4.74), 2.14 (1.00-4.57), and 2.30 (1.03-5.15), respectively. Additionally, the second quartile of perfluorododecanoic acid (PFDoA) was associated with a 3.2-fold increase in AD risk (3.24, 1.44-7.27). However, no significant associations were found in male children. CONCLUSIONS:Prenatal exposure to PFOA, PFDA, PFDoA and PFHxS significantly increased the risk of childhood AD in female children during the first 24 months of life. In addition, the associations between AD with prenatal exposure to PFNA were close to statistical significance.
| S-EPMC5773146 | biostudies-literature
Project description:Background:2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is proposed to interfere with fetal growth via altered activity of the aryl hydrocarbon receptor (protein: AHR; gene: AHR) pathway which regulates diverse biological and developmental processes including xenobiotic metabolism. Genetic variation in AHR is an important driver of susceptibility to low birthweight in children exposed to prenatal smoking, but less is known about these genetic interactions with TCDD, AHR's most potent xenobiotic ligand. Methods:The Seveso Women's Health Study (SWHS), initiated in 1996, is a cohort of 981 Italian women exposed to TCDD from an industrial explosion in July 1976. We measured TCDD concentrations in maternal serum collected close to the time of the accident. In 2008 and 2014, we followed up the SWHS cohort and collected data on birth outcomes of SWHS women with post-accident pregnancies. We genotyped 19 single nucleotide polymorphisms (SNPs) in AHR among the 574 SWHS mothers. Results:Among 901 singleton births, neither SNPs nor TCDD exposure alone were significantly associated with birthweight. However, we found six individual SNPs in AHR which adversely modified the association between maternal TCDD and birthweight, implicating gene-environment interaction. We saw an even stronger susceptibility to TCDD due to interaction when we examined the joint contribution of these SNPs in a risk allele score. These SNPs were all located in noncoding regions of AHR, particularly in proximity to the promoter. Conclusions:This is the first study to demonstrate that genetic variation across the maternal AHR gene may shape fetal susceptibilities to TCDD exposure.
| S-EPMC6280946 | biostudies-literature
Project description:The Seveso Women's Health Study (SWHS) is a historical cohort study of the female population residing near Seveso, Italy, on 10 July 1976, when a chemical explosion resulted in the highest known residential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Individual TCDD concentration was measured in serum collected near the time of the explosion, and in 1996, we collected adequate blood for TCDD and total dioxin toxic equivalent (TEQ) measurement. Polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls were measured in 1996 serum for a sample (n=225, 23%) of the SWHS cohort and WHO 2005 TEQs were calculated. We examined characteristics that predict 1996 TCDD concentrations and estimated TCDD elimination half-life over the 20-year period since the explosion. Median lipid-adjusted TCDD and total TEQ concentrations in 1996 serum were 7.3 and 26.2?p.p.t., respectively. Initial 1976 TCDD and age at explosion were the strongest predictors of 1996 TCDD. The TCDD elimination half-life was 7.1 years for women older than 10 years in 1976, but was shorter in those who were younger. Twenty years after the explosion, TCDD concentrations in this SWHS sample, the majority of who were children in 1976, remain elevated relative to background. These data add to the limited data available on TCDD elimination half-life in children.
| S-EPMC4031297 | biostudies-literature
Project description:Study questionIs in utero exposure to mercury associated with the risk of precocious puberty?Summary answerPrenatal exposure to high levels of mercury was associated with increased risk of precocious puberty, which was strengthened by concomitant maternal cardiometabolic conditions and adverse birth outcomes.What is known alreadyThe developing fetus is sensitive to mercury, a well-known endocrine disruptor which impacts the endocrine and reproductive system.Study design, size, durationThis study included 1512 mother-child pairs from the Boston Birth Cohort, a longitudinal cohort which recruited at birth and followed prospectively up to 21 years of age.Participants/materials, setting, methodsMother-child pairs, from a predominantly urban minority population, were enrolled from 2002 to 2013. Prenatal exposure was assessed by maternal mercury concentration in red blood cells (RBCs) collected at 1-3 days after delivery. Precocious puberty was defined based on International Classification of Disease codes. Cox proportional hazards models were applied to the association between maternal mercury concentrations and the risk of precocious puberty.Main results and the role of chanceThe median (interquartile range) of maternal mercury concentrations among children with and without precocious puberty were 3.4 (1.9-4.6) µg/l and 2.0 (1.0-3.7) µg/l, respectively. Compared to those in the lowest tertile for mercury, the highest tertile was associated with increased risk of precocious puberty, with an adjusted hazard ratio (HR) of 2.41, 95% CI: 1.16-5.03. In addition, concomitant maternal cardiometabolic conditions and adverse birth outcomes strengthened the effects of mercury on the risk of precocious puberty. The highest risk of precocious puberty was observed among children who had adverse birth outcomes and whose mothers had high RBC-mercury concentrations along with cardiometabolic conditions, with an HR of 4.76 (95% CI: 1.66-13.60) compared to children with favorable profiles of all three risk factors.Limitations, reasons for cautionPrecocious puberty was defined based on medical records, not on a direct assessment, which may have led to underdiagnosis and the inability to make a subclassification. The study included a predominately urban, low-income, minority population and as such our findings may not be widely generalizable.Wider implications of the findingsPrenatal Hg exposure was associated with an increased risk of precocious puberty. This risk was strengthened by concomitant maternal cardiometabolic conditions during pregnancy and adverse birth outcomes.Study funding/competing interest(s)This study was funded by the NIH/National Institute of Environmental Health Sciences, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Health Resources and Services Administration of the U.S. Department of Health and Human Services. The authors declare no conflicts of interest.Trial registration numberN/A.
| S-EPMC7891807 | biostudies-literature
Project description:BackgroundMaternal alcohol consumption in pregnancy may have adverse effects on child gross motor (GM) development. There have been few human studies on this topic, particularly ones examining low exposure. This study examined the association between prenatal alcohol exposure (PAE) and infant GM development at 12-months of age.MethodsParticipants were 1324 women recruited from antenatal clinics in Sydney and Perth, Australia. Maternal and paternal alcohol use was assessed in pregnancy via interview; offspring GM development was measured at 12-months with the Bayley Scales of Infant Development (BSID-III).ResultsAny alcohol use in pregnancy was common: 56.1%, of pregnant women drank early in Trimester one (0-6 weeks), however this reduced to 27.9% on average thereafter and at predominantly low levels. However, infant BSID GM scale scores were not found to differ significantly as a function of PAE in the first 6-weeks (low, moderate, binge or heavy PAE), nor with low PAE across pregnancy.ConclusionsWe found no evidence to suggest that low PAE is associated with measurable impairment in infant GM development at 12-months. Further research is needed to examine potential PAE impacts on GM development in heavier exposure groups and through the childhood years when subtle GM deficits may be more detectable.
| S-EPMC6515673 | biostudies-literature
Project description:Background: How prenatal smoke exposure affects DNA methylation leading to atopic disorders remains to be addressed. Epigenetic biomarkers informative of prenatal smoke exposure and atopic disorders are wanting. Since most children suffering from atopic dermatitis (AD) continue to develop asthma later in life, we explored whether prenatal smoke exposure e induces DNA methylation and searched for predictive epigenetic biomarkers for smoke related atopic disorders. Methods: Methylation differences associated with smoke exposure were screened by Illumina methylation panel for children from the Taiwan birth panel study cohort initially. Information about development of atopic dermatitis (AD) and risk factors were collected. Cord blood cotinine levels were measured to represent prenatal smoke exposure. CpG loci that demonstrated a statistically significant difference in methylation were validated by methylation-dependent fragment separation (MDFS). Differential methylation in three genes (TSLP, GSTT1, and CYB5R3) was identified through the screen and their functions were investigated. Results: Among these, only thymic stromal lymphopoietin (TSLP) gene displayed significant difference in promoter methylation percentage after being validated by MDFS (p=0.029). TSLP gene was further investigated in a larger sample of 92 children from the cohort. Methylation status of the TSLP 5′-CpG island (CGI) was found to be significantly associated with prenatal smoke exposure (OR=3.59, 95%CI=1.49-8.64; cotinine level 0.10 ng/ml, sensitivity= 77%; specificity = 61%) and with AD (OR=4.77, 95%CI=1.47-15.53). The degree of TSLP 5′CGI methylation inversely correlated with TSLP protein expression levels (per unit: β=－6.69 ng/ml; 95% CIs, －12.80~－0.59; p=0.032). Conclusions: The effect of prenatal tobacco smoke exposure on the risk for AD may be mediated through DNA methylation. Cord blood methylated TSLP 5′CGI may be a potential epigenetic biomarker for environmentally-related atopic disorders. The buffy coat and plasma samples were separated and stored at −80°C. DNA (100 ng-500 ng) was extracted from cord white blood cells. Microarrays have been performed to investigate fourteen samples, which were classified as two groups according to cotinine exposure dosage (7 versus 7 : high exposure verses low exposure).
2013-12-31 | E-GEOD-35222 | biostudies-arrayexpress