Jesús Ibarluzea

Breast cancer risk and the combined effect of environmental estrogens.

AbstractObjective: The present study aimed to determine whether the combined effects of environmental estrogens measured as the total effective xenoestrogen burden (TEXB-alpha) are a risk factor for breast cancer over and above the risk potentially linked to specific pesticides. Methods: We measured the levels of 16 organochlorine pesticides as well as TEXB in adipose tissue of 198 women at the time of breast cancer diagnosis. These were compared with findings in 260 age and hospital matched control women without breast cancer. Results: The median levels of p,p′-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), aldrin, endosulfan ether and lindane (the pesticides detected in >40% of the study population) were higher in cases than controls, although the differences did not reach statistical significance. After adjusting for potential confounders, the odds ratio (OR) for breast cancer in women with detectable levels of aldrin was 1.55 (95% confidence interval (CI) 1.00–2.40). Among the postmenopausal women, the OR for aldrin and lindane was 1.84 (95% CI 1.06–3.18) and 1.76 (95% CI 1.04–2.98), respectively. Among cases with body mass index (BMI) below the median (28.6 kg/m2), the OR was 3.42 (95% CI 1.22–9.58) for women in the highest quartile of TEXB-alpha versus those in the lowest. The subgroup of leaner postmenopausal women showed an increased risk (OR: 5.67; 95% CI 1.59–20.21) for those in the highest tertile versus those in the lowest. Conclusions: We found an increased risk for breast cancer in the leaner women, especially in the leaner postmenopausal subgroup, related to the TEXB-alpha. The pesticides aldrin and lindane are also individually associated with risk.

Human exposure to endocrine disrupters: Standardisation of a marker of estrogenic exposure in adipose tissue

In many epidemiological studies based on the direct measurement of exposure to organochlorines, the chemicals of concern are determined directly from adipose tissue samples. Although the measurement of all possible organochlorines, their metabolites, isomers and congeners may be desirable, it is expensive and time‐consuming and many chemicals with hormonal activity may not yet have been identified. Testing systems are therefore required to screen for estrogenicity and to identify appropriate biomarkers of human exposure. To address this issue, we developed and standardised a method to assess the total estrogenic xenobiotic burden in human adipose tissue. The method extracts and separates the more lipophilic xenoestrogens from ovarian estrogens, with a subsequent bioassay determination of the cumulative effect of the xenoestrogens. It was applied to 400 women, using 200 mg of adipose tissue: 65% of samples showed measurable estrogenicity in the fraction where most non‐polar xenoestrogens eluted, and 76% of fractions where ovarian estrogens eluted were positive for estrogenicity. Residues of 16 organochlorine pesticides were determined. No correlation was found between pesticide content and estrogenicity of the samples. The high percentage of positive samples suggests that the method is sensitive enough to be used as a biomarker of human exposure to estrogenic xenobiotics and can be applied in epidemiological studies.

Iodine Intake and Maternal Thyroid Function During Pregnancy

Background: An adequate iodine intake during pregnancy is essential for the synthesis of maternal thyroid hormones and normal brain development in the fetus. Scant evidence is available on the effects and safety of iodine supplementation during pregnancy in areas with adequate or mildly deficient iodine intake. We examined the association of maternal iodine intake and supplementation with thyroid function before 24 weeks of gestation in population-based samples from 3 different areas in Spain. Methods: A cross-sectional study of 1844 pregnant women (gestational age range 8–23 weeks) was carried out in 3 areas in Spain (Guipúzcoa, Sabadell, Valencia), during the period 2004–2008. We measured levels of free thyroxine and thyroid-stimulating hormone (TSH) in serum, iodine in a spot urine sample, and questionnaire estimates of iodine intake from diet, iodized salt and supplements. Adjusted associations were assessed by multiple linear regression and logistic regression analyses. Results: There was an increased risk of TSH above 3 &mgr;U/mL in women who consumed 200 &mgr;g or more of iodine supplements daily compared with those who consumed less than 100 &mgr;g/day (adjusted odds ratio = 2.5 [95% confidence interval = 1.2 to 5.4]). We observed no association between urinary iodine and TSH levels. Pregnant women from the area with the highest median urinary iodine (168 &mgr;g/L) and highest supplement coverage (93%) showed the lowest values of serum free thyroxine. (geometric mean = 10.09 pmol/L [9.98 to 10.19]). Conclusions: Iodine supplement intake in the first half of pregnancy may lead to maternal thyroid dysfunction in iodine-sufficient or mildly iodine-deficient populations.

Circulating 25-Hydroxyvitamin D3 in Pregnancy and Infant Neuropsychological Development

OBJECTIVE: To investigate whether circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration in pregnancy is associated with neuropsychological development in infants. METHODS: The Spanish population-based cohort study INfancia y Medio Ambiente Project recruited pregnant women during the first trimester of pregnancy between November 2003 and February 2008. Completed data on 1820 mother-infant pairs were used. Maternal plasma 25(OH)D3 concentration was measured by high-performance liquid chromatography in pregnancy (mean 13.5±2.1 weeks of gestation). Offspring mental and psychomotor scores were assessed by trained psychologists at age 14 months (range, 11–23) by using the Bayley Scales of Infant Development. β-Coefficients with 95% confidence intervals (CIs) of mental and psychomotor scores associated with continuous or categorical concentrations of maternal plasma 25(OH)D3 were calculated by using linear regression analysis. RESULTS: The median plasma value of 25(OH)D3 in pregnancy was 29.6 ng/mL (interquartile range, 21.8–37.3). A positive linear relationship was found between circulating concentrations of maternal 25(OH)D3 concentrations in pregnancy and mental and psychomotor scores in the offspring. After adjustment for potential confounders, infants of mothers with 25(OH)D3 concentrations in pregnancy >30 ng/mL showed higher mental score (β = 2.60; 95% CI 0.63–4.56) and higher psychomotor score (β = 2.32; 95% CI 0.36–4.28) in comparison with those of mothers with 25(OH)D3 concentrations <20 ng/mL. CONCLUSIONS: Higher circulating concentration of maternal 25(OH)D3 in pregnancy was associated with improved mental and psychomotor development in infants.

Prenatal Exposure to Mercury and Infant Neurodevelopment in a Multicenter Cohort in Spain: Study of Potential Modifiers

Vulnerability of the central nervous system to mercury is increased during early development. This study aimed to evaluate whether cord blood total mercury levels may have a negative effect on both mental and psychomotor development in a maternal-birth cohort from moderate-high fish consumption areas. Study subjects were 1,683 child participants in the INMA (Environment and Childhood) Project from 4 areas of Spain between 2003 and 2010. Cord blood total mercury levels were analyzed by atomic absorption spectrometry. Infant neurodevelopment was assessed around age 14 months by the Bayley Scales of Infant Development. Sociodemographic, lifestyle, and dietary information was obtained by questionnaire during pregnancy. The geometric mean of total mercury levels was 8.4 μg/L (95% confidence interval (CI): 8.1, 8.7). In multivariate analysis, a doubling in total mercury levels did not show an association with mental (β = 0.1, 95% CI: -0.68, 0.88) or psychomotor (β = -0.05, 95% CI: -0.79, 0.68) developmental delay; however, stratified findings by sex suggest a negative association between prenatal exposure to total mercury and psychomotor development among female infants (β = -1.09, 95% CI: -2.21, 0.03), although follow-up is required to confirm these results.

Urinary 1-hydroxypyrene and PAH exposure in 4-year-old Spanish children

AIMS Exposure to polycyclic aromatic hydrocarbons (PAH), among the main compounds present in polluted urban air, is of concern for childrens health. Childhood exposure to PAH was assessed by urinary monitoring of 1-hydroxypyrene (1-OHP), a pyrene metabolite, investigating its association with exposure to air pollution and other factors related to PAH in air. METHODS A group of 174 4-year-old children were recruited and a questionnaire on their indoor and outdoor residential environment was completed by parents. At the same time, environmental measurements of traffic-related air pollution (NO2) were carried out. A urine sample was collected from each child in order to analyze 1-OHP using HPLC with fluorescence detection, correcting for creatinine concentrations. Non-parametric tests and regression analyses were used to identify environmental factors that influence 1-OHP excretion. RESULTS Mean urinary 1-OHP concentration was 0.061 micromol/mol creatinine, ranging from 0.004 to 0.314 micromol/mol. Non-parametric tests and regression analysis showed positive and significant associations (P<or=0.05) between 1-OHP and predicted residential exposure to NO2 (which was based on outdoor environmental measurements and geo-statistical analysis), self-reported residential vehicle traffic, passive smoking and cooking appliance. 1-OHP levels tended to be higher among children living in urban areas (0.062 micromol/mol vs. 0.058 micromol/mol for children living in rural areas) but differences were not significant (P=0.20). CONCLUSION In Southern Spain, concentrations of urinary 1-OHP were in the lower range of those generally reported for children living in non-polluted areas in Western Europe and the USA. Traffic-related air pollution, passive smoking and cooking appliance influenced urinary 1-OHP level in the children, which should be prevented due to the health consequences of the inadvertent exposure to PAH during development.

Prenatal mercury exposure in a multicenter cohort study in Spain

BACKGROUND Mercury is a ubiquitous heavy metal that may negatively affect human health. It is desirable to investigate mercury exposure in vulnerable populations. OBJECTIVE To determine the concentrations of total mercury (T-Hg) in cord blood and to evaluate the role of maternal fish consumption in a Spanish mother and child cohort. METHODS A total of 1883 mother and child pairs from a population-based cohort were included between 2004 and 2008. T-Hg concentrations were measured in whole cord blood and maternal seafood consumption was ascertained by means of a food-frequency questionnaire. Linear regression was used in stratified analyses, while a joint model was adjusted using a mixed-effects linear model. RESULTS Maternal daily seafood consumption was 78g/d and the geometric mean for T-Hg was 8.2μg/L. Maternal fish intake during pregnancy, mothers age, country of origin, educational level, employment status and parity, as well as area of study and season of delivery, were associated with cord blood T-Hg levels. A doubling in consumption of large oily fish was associated with an increase of 11.4% (95%CI: 3.8 to 19.6%) in cord blood T-Hg levels, followed by an increase of 8.4% (95%CI: 5.7 to 11.2%) in the case of canned tuna and 8.3% (95%CI: 5.5 to 11.1%) in that of lean fish. CONCLUSION A high proportion of newborns had elevated concentrations of cord blood T-Hg according to the current US-EPA reference dose (5.8μg/L for methylmercury). Mercury concentrations were related to maternal fish consumption, with large oily fish being the main contributor.

Early growth characteristics and the risk of reduced lung function and asthma : A meta-analysis of 25,000 children

BACKGROUND Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Prenatal exposure to persistent organic pollutants and rapid weight gain and overweight in infancy

To examine the effects of prenatal exposure to persistent organic pollutants (POPs) on rapid growth in the first 6 months of life and overweight at 14 months of age.

Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies: The ESCAPE project

Background Prenatal exposure to air pollutants has been suggested as a possible etiologic factor for the occurrence of autism spectrum disorder. Objectives We aimed to assess whether prenatal air pollution exposure is associated with childhood autistic traits in the general population. Methods Ours was a collaborative study of four European population-based birth/child cohorts—CATSS (Sweden), Generation R (the Netherlands), GASPII (Italy), and INMA (Spain). Nitrogen oxides (NO2, NOx) and particulate matter (PM) with diameters of ≤ 2.5 μm (PM2.5), ≤ 10 μm (PM10), and between 2.5 and 10 μm (PMcoarse), and PM2.5 absorbance were estimated for birth addresses by land-use regression models based on monitoring campaigns performed between 2008 and 2011. Levels were extrapolated back in time to exact pregnancy periods. We quantitatively assessed autistic traits when the child was between 4 and 10 years of age. Children were classified with autistic traits within the borderline/clinical range and within the clinical range using validated cut-offs. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. Results A total of 8,079 children were included. Prenatal air pollution exposure was not associated with autistic traits within the borderline/clinical range (odds ratio = 0.94; 95% CI: 0.81, 1.10 per each 10-μg/m3 increase in NO2 pregnancy levels). Similar results were observed in the different cohorts, for the other pollutants, and in assessments of children with autistic traits within the clinical range or children with autistic traits as a quantitative score. Conclusions Prenatal exposure to NO2 and PM was not associated with autistic traits in children from 4 to 10 years of age in four European population-based birth/child cohort studies. Citation Guxens M, Ghassabian A, Gong T, Garcia-Esteban R, Porta D, Giorgis-Allemand L, Almqvist C, Aranbarri A, Beelen R, Badaloni C, Cesaroni G, de Nazelle A, Estarlich M, Forastiere F, Forns J, Gehring U, Ibarluzea J, Jaddoe VW, Korek M, Lichtenstein P, Nieuwenhuijsen MJ, Rebagliato M, Slama R, Tiemeier H, Verhulst FC, Volk HE, Pershagen G, Brunekreef B, Sunyer J. 2016. Air pollution exposure during pregnancy and childhood autistic traits in four European population-based cohort studies: the ESCAPE Project. Environ Health Perspect 124:133–140; http://dx.doi.org/10.1289/ehp.1408483