Nina Iszatt

Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study.

Background Hypospadias is one of the most common urogenital congenital anomalies affecting baby boys. Prevalence estimates in Europe range from 4 to 24 per 10,000 births, depending on definition, with higher rates reported from the United States. Relatively little is known about potential risk factors, but a role for endocrine-disrupting chemicals (EDCs) has been proposed. Objective Our goal was to elucidate the risk of hypospadias associated with occupational exposure of the mother to endocrine-disruptor chemicals, use of folate supplementation during pregnancy, and vegetarianism. Design We designed a case–control study of 471 hypospadias cases referred to surgeons and 490 randomly selected birth controls, born 1 January 1997–30 September 1998 in southeast England. Telephone interviews of mothers elicited information on folate supplementation during pregnancy and vegetarianism. We used a job exposure matrix to classify occupational exposure. Results In multiple logistic regression analysis, there were increased risks for self-reported occupational exposure to hair spray [exposed vs. nonexposed, odds ratio (OR) = 2.39; 95% confidence interval (CI), 1.40–4.17] and phthalate exposure obtained by a job exposure matrix (OR = 3.12; 95% CI, 1.04–11.46). There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64; 95% CI, 0.44–0.93). Vegetarianism was not associated with hypospadias risk. Conclusions Excess risks of hypospadias associated with occupational exposures to phthalates and hair spray suggest that antiandrogenic EDCs may play a role in hypospadias. Folate supplementation in early pregnancy may be protective.

The epidemiology and possible mechanisms of disinfection by-products in drinking water.

This paper summarizes the epidemiological evidence for adverse health effects associated with disinfection by-products (DBPs) in drinking water and describes the potential mechanism of action. There appears to be good epidemiological evidence for a relationship between exposure to DBPs, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but the evidence for other cancers including colorectal cancer is inconclusive and inconsistent. There appears to be some evidence for an association between exposure to DBPs, specifically THMs, and little for gestational age/intrauterine growth retardation and, to a lesser extent, pre-term delivery, but evidence for relationships with other outcomes such as low birth weight, stillbirth, congenital anomalies and semen quality is inconclusive and inconsistent. Major limitations in exposure assessment, small sample sizes and potential biases may account for the inconclusive and inconsistent results in epidemiological studies. Moreover, most studies have focused on total THMs as the exposure metric, whereas other DBPs appear to be more toxic than the THMs, albeit generally occurring at lower levels in the water. The mechanisms through which DBPs may cause adverse health effects including cancer and adverse reproductive effects have not been well investigated. Several mechanisms have been suggested, including genotoxicity, oxidative stress, disruption of folate metabolism, disruption of the synthesis and/or secretion of placental syncytiotrophoblast-derived chorionic gonadotropin and lowering of testosterone levels, but further work is required in this area.

Chlorination disinfection by-products in drinking water and congenital anomalies: review and meta-analyses.

Objectives The aim of this study was to review epidemiologic evidence, provide summary risk estimates of the association between exposure to chlorination disinfection by-products (DBPs) and congenital anomalies, and provide recommendations for future studies. Data sources and extraction We included all published epidemiologic studies that evaluated a relationship between an index of DBP exposure (treatment, water source, DBP measurements, and both DBP measurements and personal characteristics) and risk of congenital anomalies. When three or more studies examined the same exposure index and congenital anomaly, we conducted a meta-analysis to obtain a summary risk estimate comparing the highest exposure group with the lowest exposure group. When five or more studies examined total trihalomethane (TTHM) exposure and a specific congenital anomaly, we conducted a meta-analysis to obtain exposure–response risk estimates per 10 μg/L TTHM. Data synthesis For all congenital anomalies combined, the meta-analysis gave a statistically significant excess risk for high versus low exposure to water chlorination or TTHM [17%; 95% confidence interval (CI), 3–34] based on a small number of studies. The meta-analysis also suggested a statistically significant excess risk for ventricular septal defects (58%; 95% CI, 21–107), but this was based on only three studies, and there was little evidence of an exposure–response relationship. We observed no statistically significant relationships in the other meta-analyses. We found little evidence for publication bias, except for urinary tract defects and cleft lip and palate. Conclusion Although some individual studies have suggested an association between chlorination disinfection by-products and congenital anomalies, meta-analyses of all currently available studies demonstrate little evidence of such an association.

Health impacts of long-term exposure to disinfection by-products in drinking water in Europe: HIWATE

There appears to be very good epidemiological evidence for a relationship between chlorination by-products, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but the evidence for other cancers, including colorectal cancer appears to be inconclusive and inconsistent. There appears to be some evidence for a relationship between chlorination by-products, as measured by THMs, and small for gestational age (SGA)/intrauterine growth retardation (IUGR) and preterm delivery, but evidence for other outcomes such as low birth weight (LBW), stillbirth, congenital anomalies and semen quality appears to be inconclusive and inconsistent.The overall aim of the HIWATE study is to investigate potential human health risks (e.g. bladder and colorectal cancer, premature births, SGA, semen quality, stillbirth, congenital anomalies) associated with long-term exposure to low levels of disinfectants (such as chlorine) and DBPs occurring in water for human consumption and use in the food industry. The study will comprise risk-benefit analyses including quantitative assessments of risk associated with microbial contamination of drinking water versus chemical risk and will compare alternative treatment options. The outcome will be improved risk assessment and better information for risk management. The work is divided into different topics (exposure assessment, epidemiology, risk assessment and management) and studies.

Novel Developmental Analyses Identify Longitudinal Patterns of Early Gut Microbiota that Affect Infant Growth

It is acknowledged that some obesity trajectories are set early in life, and that rapid weight gain in infancy is a risk factor for later development of obesity. Identifying modifiable factors associated with early rapid weight gain is a prerequisite for curtailing the growing worldwide obesity epidemic. Recently, much attention has been given to findings indicating that gut microbiota may play a role in obesity development. We aim at identifying how the development of early gut microbiota is associated with expected infant growth. We developed a novel procedure that allows for the identification of longitudinal gut microbiota patterns (corresponding to the gut ecosystem developing), which are associated with an outcome of interest, while appropriately controlling for the false discovery rate. Our method identified developmental pathways of Staphylococcus species and Escherichia coli that were associated with expected growth, and traditional methods indicated that the detection of Bacteroides species at day 30 was associated with growth. Our method should have wide future applicability for studying gut microbiota, and is particularly important for translational considerations, as it is critical to understand the timing of microbiome transitions prior to attempting to manipulate gut microbiota in early life.

Prenatal and postnatal exposure to persistent organic pollutants and Infant growth: A pooled analysis of seven european birth cohorts

Background Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern between prenatal and postnatal effects. Objectives We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity). Methods We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p,p´-dichlorodiphenyldichloroethylene (p,p´-DDE) (n = 1,864), estimating prenatal and postnatal POPs exposure using a validated pharmacokinetic model. Growth was change in weight-for-age z-score between birth and 24 months. Per compound, multilevel models were fitted with either POPs total exposure from conception to 24 months or prenatal or postnatal exposure. Results We found a significant increase in growth associated with p,p´-DDE, seemingly due to prenatal exposure (per interquartile increase in exposure, adjusted β = 0.12; 95% CI: 0.03, 0.22). Due to heterogeneity across cohorts, this estimate cannot be considered precise, but does indicate that an association with infant growth is present on average. In contrast, a significant decrease in growth was associated with postnatal PCB-153 exposure (β = –0.10; 95% CI: –0.19, –0.01). Conclusion To our knowledge, this is the largest study to date of POPs exposure and infant growth, and it contains state-of-the-art exposure modeling. Prenatal p,p´-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels. Citation Iszatt N, Stigum H, Verner MA, White RA, Govarts E, Palkovicova Murinova L, Schoeters G, Trnovec T, Legler J, Pelé F, Botton J, Chevrier C, Wittsiepe J, Ranft U, Vandentorren S, Kasper-Sonnenberg M, Klümper C, Weisglas-Kuperus N, Polder A, Eggesbø M, OBELIX. 2015. Prenatal and postnatal exposure to persistent organic pollutants and infant growth: a pooled analysis of seven European birth cohorts. Environ Health Perspect 123:730–736; http://dx.doi.org/10.1289/ehp.1308005

Fish intake in pregnancy and child growth: A pooled analysis of 15 European and US birth cohorts

IMPORTANCE Maternal fish intake in pregnancy has been shown to influence fetal growth. The extent to which fish intake affects childhood growth and obesity remains unclear. OBJECTIVE To examine whether fish intake in pregnancy is associated with offspring growth and the risk of childhood overweight and obesity. DESIGN, SETTING, AND PARTICIPANTS Multicenter, population-based birth cohort study of singleton deliveries from 1996 to 2011 in Belgium, France, Greece, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Spain, and Massachusetts. A total of 26,184 pregnant women and their children were followed up at 2-year intervals until the age of 6 years. EXPOSURES Consumption of fish during pregnancy. MAIN OUTCOMES AND MEASURES We estimated offspring body mass index percentile trajectories from 3 months after birth to 6 years of age. We defined rapid infant growth as a weight gain z score greater than 0.67 from birth to 2 years and childhood overweight/obesity at 4 and 6 years as body mass index in the 85th percentile or higher for age and sex. We calculated cohort-specific effect estimates and combined them by random-effects meta-analysis. RESULTS This multicenter, population-based birth cohort study included the 26,184 pregnant women and their children. The median fish intake during pregnancy ranged from 0.5 times/week in Belgium to 4.45 times/week in Spain. Women who ate fish more than 3 times/week during pregnancy gave birth to offspring with higher body mass index values from infancy through middle childhood compared with women with lower fish intake (3 times/week or less). High fish intake during pregnancy (>3 times/week) was associated with increased risk of rapid infant growth, with an adjusted odds ratio (aOR) of 1.22 (95% CI, 1.05-1.42) and increased risk of offspring overweight/obesity at 4 years (aOR, 1.14 [95% CI, 0.99-1.32]) and 6 years (aOR, 1.22 [95% CI, 1.01-1.47]) compared with an intake of once per week or less. Interaction analysis showed that the effect of high fish intake during pregnancy on rapid infant growth was greater among girls (aOR, 1.31 [95% CI, 1.08-1.59]) than among boys (aOR, 1.11 [95% CI, 0.92-1.34]; P = .02 for interaction). CONCLUSIONS AND RELEVANCE High maternal fish intake during pregnancy was associated with increased risk of rapid growth in infancy and childhood obesity. Our findings are in line with the fish intake limit proposed by the US Food and Drug Administration and Environmental Protection Agency.

Water Consumption and Use, Trihalomethane Exposure, and the Risk of Hypospadias

OBJECTIVES: Hypospadias is a congenital anomaly that affects up to 70 in 10 000 males. Ingestion of drinking-water–disinfection byproducts such as trihalomethanes (THMs) has been associated with hypospadias in a small sample. We examined risk of hypospadias and exposure to THMs through water consumption and use. METHODS: Between September 2000 and March 2003, we interviewed mothers of 471 boys with hypospadias and 490 controls in southeast England about maternal water consumption, dishwashing, showering, bathing and swimming. We obtained residential THM concentrations from the water companies and linked them by using Geographical Information Systems, which provided data on 468 case-subjects and 485 controls. RESULTS: THM exposures, except for ingestion of ≥6 μg/day of bromodichloromethane (odds ratio [OR]: 1.65 [95% confidence interval (CI): 1.02–2.69]), were not associated with risk of hypospadias. Elevated risk of hypospadias was associated with estimates of consumption of cold tap water at home (OR: 1.71 [95% CI: 1.07–2.76]), total water (OR: 1.70 [95% CI: 1.09–2.67]), bottled water (OR: 1.64 [95% CI: 1.09–2.48]), and total fluid (OR: 1.55 [95% CI: 1.01–2.39]) for the highest versus the lowest categories; the first 2 showed dose-response trends. CONCLUSIONS: Evidence for an association between maternal water consumption and risk of hypospadias did not seem to be explained by THM exposure. Factors that influence maternal water consumption or other contaminants in tap or bottled water might explain this finding. It is important that women maintain an adequate fluid intake during pregnancy.

Use of biocides and insect repellents and risk of hypospadias.

Background The relationship between the use of biocides and insect repellents and the risk of hypospadias was examined in a large case–control study in the South East of England. Methods A case–control study was carried out among 471 cases of hypospadias referred to surgeons, and 490 randomly selected population-based controls, born between 1 January 1997 and 30 September 1998. Telephone interviews were conducted between September 2000 and March 2003. The questionnaire included information on demographic, lifestyle and environmental factors, including the use of biocides and insect repellents, during pregnancy. A total biocide score was created from summing positive responses to an eight-item biocide exposure questionnaire. Results The use of insect repellent (adjusted OR 1.81, 95% CI 1.06 to 3.11) during the first trimester of pregnancy was associated with risk of hypospadias, but none of the biocides, or indicators for them, except for the total biocide score for the highest two exposure categories (score 3: adjusted OR 1.73, 95% CI 1.02 to 2.94; and scores 4 and 5 combined: adjusted OR 2.98, 95% CI 1.01 to 8.78) showed statistically significant associations. Conclusion The authors found an association between the use of insect repellent and total biocide score and risk of hypospadias. In particular, the use of insect repellent warrants further investigation, specifically in relation to type, content and frequency of use since this information was missing in the current study.

Perinatal exposure to dioxins and dioxin-like compounds and infant growth and body mass index at seven years: A pooled analysis of three European birth cohorts.

BACKGROUND Dioxins and dioxin-like compounds are endocrine disrupting chemicals (EDCs). Experimental studies suggest perinatal exposure to EDCs results in later obesity. However, the few epidemiological investigations on dioxins are inconclusive. We investigated perinatal exposure to dioxins and dioxin-like compounds, infant growth and body mass index (BMI) in childhood. METHODS We pooled data from 3 European birth cohorts (Belgian, Norwegian, Slovak) with exposure assessment in cord blood or breast milk. Two cohorts had dioxin-like toxicity assessed using dioxin-responsive chemical-activated luciferase expression (DR-CALUX) bioassay and one cohort had measured concentrations of dioxins, furans and dioxin-like polychlorinated biphenols with CALUX relative potency values applied. Growth was cohort- and sex-specific change in weight-for-age z-score between birth and 24months (N=367). BMI was calculated at around 7years (median 7.17, interquartile range [IQR] 7.00-7.37years, N=251), and overweight defined according to international standards for children equivalent to adult BMI >25kg/m(2) (Cole and Lobstein, 2012). We fitted multivariate models using generalized estimating equations, and tested effect modification by sex, breastfeeding and cohort. Results per 10pgCALUXTEQ/g lipid increase in exposure. RESULTS Dioxin exposure was highest in the Belgian and lowest in the Norwegian cohort; median (IQR) of the pooled sample 13 (12.0) pgCALUXTEQ/g lipid. Perinatal exposure to dioxins and dioxin-like compounds appeared associated with increased growth between 0 and 24months (adjusted estimate for change in z-score: β=0.07, 95% CI: -0.01, 0.14). At 7years, dioxins exposure was associated with a statistically significant increase in BMI in girls (adjusted estimate for BMI units β=0.49, 95% CI: 0.07, 0.91) but not in boys (β=-0.03, 95% CI: -0.55, 0.49) (p-interaction=0.044). Furthermore, girls had a 54% (-6%, 151%) increased risk of overweight at 7years (p-interaction=0.023). CONCLUSION Perinatal exposure to dioxin and dioxin-like compounds was associated with increased early infant growth, and increased BMI in school age girls. Studies in larger sample sizes are required to confirm these sex-specific effects.