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Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin.

ABSTRACT: Neonatal hypothyroidism has been associated in animal models with maternal exposure to several environmental contaminants; however, evidence for such an association in humans is inconsistent. We evaluated whether maternal exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent and widespread toxic environmental contaminant, is associated with modified neonatal thyroid function in a large, highly exposed population in Seveso, Italy.Between 1994 and 2005, in individuals exposed to TCDD after the 1976 Seveso accident we conducted: (i) a residence-based population study on 1,014 children born to the 1,772 women of reproductive age in the most contaminated zones (A, very high contamination; B, high contamination), and 1,772 age-matched women from the surrounding noncontaminated area (reference); (ii) a biomarker study on 51 mother-child pairs for whom recent maternal plasma dioxin measurements were available. Neonatal blood thyroid-stimulating hormone (b-TSH) was measured on all children. We performed crude and multivariate analyses adjusting for gender, birth weight, birth order, maternal age, hospital, and type of delivery. Mean neonatal b-TSH was 0.98 microU/ml (95% confidence interval [CI] 0.90-1.08) in the reference area (n = 533), 1.35 microU/ml (95% CI 1.22-1.49) in zone B (n = 425), and 1.66 microU/ml (95% CI 1.19-2.31) in zone A (n = 56) (p < 0.001). The proportion of children with b-TSH > 5 microU/ml was 2.8% in the reference area, 4.9% in zone B, and 16.1% in zone A (p < 0.001). Neonatal b-TSH was correlated with current maternal plasma TCDD (n = 51, beta = 0.47, p < 0.001) and plasma toxic equivalents of coplanar dioxin-like compounds (n = 51, beta = 0.45, p = 0.005).Our data indicate that environmental contaminants such as dioxins have a long-lasting capability to modify neonatal thyroid function after the initial exposure.

SUBMITTER: Baccarelli A

PROVIDER: S-EPMC2488197 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin.

Baccarelli Andrea A Giacomini Sara M SM Corbetta Carlo C Landi Maria Teresa MT Bonzini Matteo M Consonni Dario D Grillo Paolo P Patterson Donald G DG Pesatori Angela C AC Bertazzi Pier Alberto PA

PLoS medicine 20080701 7

<h4>Background</h4>Neonatal hypothyroidism has been associated in animal models with maternal exposure to several environmental contaminants; however, evidence for such an association in humans is inconsistent. We evaluated whether maternal exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent and widespread toxic environmental contaminant, is associated with modified neonatal thyroid function in a large, highly exposed population in Seveso, Italy.<h4>Methods and findings</h4>Betw ...[more]

PMID: 18666825

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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.

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.

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.

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.

Project description:Study questionIs there an association between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and fecundability and infertility among Seveso women and their daughters?Summary answerTCDD exposure is associated with a decrease in fecundability and increased risk of infertility in women, as well as their daughters.What is known alreadyIn animal studies, maternal exposure to TCDD is associated with decreased fertility in offspring. Effects of TCDD are mediated by activation of the aryl hydrocarbon receptor (AHR) pathway.Study design, size, durationThe Seveso Women's Health Study (SWHS) has followed 981 women exposed to TCDD in a 1976 accident since 1996. In 2014, we initiated the Seveso Second Generation Study to follow-up their children.Participants/materials, setting, methodsWe obtained information on pregnancy history including time of trying to conceive from SWHS women and their daughters who were 18 years or older. We considered TCDD exposure as initial 1976 serum TCDD concentration and estimated TCDD at pregnancy. We examined relationships of TCDD exposure with time to pregnancy (TTP, the monthly probability of conception within the first 12 months of trying) and infertility (≥12 months of trying to conceive). We also assessed contributions of polymorphisms in the AHR pathway via genetic risk score.Main results and the role of chanceAmong SWHS women (n = 446), median TTP was 3 months and 18% reported taking ≥12 months to conceive. Initial 1976 TCDD (log10) was associated with longer TTP (adjusted fecundability odds ratio = 0.82; 95% CI 0.68-0.98) and increased risk of infertility (adjusted relative risk = 1.35; 95% CI 1.01-1.79). TCDD at pregnancy yielded similar associations. Among SWHS daughters (n = 66), median TTP was 2 months and 11% reported taking ≥12 months to conceive. Daughters showed similar, but non-significant, associations with maternal TCDD exposure.Limitations, reasons for cautionA limitation of this study is time to pregnancy was reported retrospectively, although previous studies have found women are able to recall time to conception with a high degree of accuracy many years after the fact. The number of SWHS daughters who had a live birth was small and we were unable to examine fecundability of SWHS sons.Wider implications of the findingsConsistent with previous findings in animal studies, our study found that TCDD exposure may be associated with decreased fertility in Seveso mothers and potentially in their daughters exposed in utero. There may be susceptible genetic subgroups. The literature has largely considered the genetics of the AHR pathway in the context of male fertility but not female fertility, despite strong biological plausibility. These findings should be replicated in larger populations and of different ancestry. Future studies in Seveso should examine the sons and the grandchildren of exposed mothers given the animal literature suggesting potential heritable epigenetic effects.Study funding/competing interest(s)This study was supported by grant numbers F06 TW02075-01 from the National Institutes of Health, R01 ES07171 and 2P30-ESO01896-17 from the National Institute of Environmental Health Sciences, R82471 from the U.S. Environmental Protection Agency and #2896 from Regione Lombardia and Fondazione Lombardia Ambiente, Milan, Italy. J.A. was supported by F31ES026488 from the National Institutes of Health. The authors declare they have no actual or potential competing financial interests.Trial registration numberN/A.

Project description:BackgroundMaternal and neonatal thyroid function is critical for growth and neurodevelopment. Exposure to individual per- and polyfluoroalkyl substances (PFAS) can alter circulating thyroid hormone levels, but few studies have investigated effects of combined exposure to multiple PFAS.ObjectivesEstimate associations of exposure to multiple PFAS during early pregnancy with maternal and neonatal thyroid function.MethodsThe study population consisted of 726 mothers and 465 neonates from Project Viva, a Boston, Massachusetts area longitudinal pre-birth cohort. We measured six PFAS [perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), perfluorohexane sulfonate (PFHxS), 2-(N-ethyl-perfluorooctane sulfonamido)acetate (EtFOSAA), and 2-(N-methyl-perfluorooctane sulfonamido)acetate (MeFOSAA)] and thyroxine (T4), Free T4 Index (FT4I), and thyroid stimulating hormone (TSH) in maternal plasma samples collected during early pregnancy, and neonatal T4 in postpartum heel sticks. We estimated individual and joint effects of PFAS exposure with thyroid hormone levels using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR), and evaluated potential non-linearity and interactions among PFAS using BKMR.ResultsHigher concentrations of the PFAS mixture were associated with significantly lower maternal FT4I, with MeFOSAA, EtFOSAA, PFOA, and PFHxS contributing most to the overall mixture effect in BKMR and WQS regression. In infants, higher concentrations of the PFAS mixture were associated with lower T4 levels, primarily in males, with PFHxS and MeFOSAA contributing most in WQS, and PFHxS contributing most in BKMR. The PFAS mixture was not associated with maternal T4 or TSH levels. However, in maternal BKMR analyses, ln-PFOS was positively associated with T4 levels (Δ25th to 75th percentile: 0.21 µg/dL; 95% credible interval: -0.03, 0.47) and ln-PFHxS was associated with a non-linear effect on TSH levels.ConclusionsThese findings support the hypothesis that there may be combined effects of prenatal exposure to multiple PFAS on maternal and neonatal thyroid function, but the direction and magnitude of these effects may vary across individual PFAS.

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Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin.

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Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin.

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