Mònica Guxens

Effect of a traditional Mediterranean diet on lipoprotein oxidation: a randomized controlled trial.

BACKGROUND Despite the richness in antioxidants of the Mediterranean diet, to our knowledge, no randomized controlled trials have assessed its effect on in vivo lipoprotein oxidation. METHODS A total of 372 subjects at high cardiovascular risk (210 women and 162 men; age range, 55-80 years), who were recruited into a large, multicenter, randomized, controlled, parallel-group clinical trial (the Prevención con Dieta Mediterránea [PREDIMED] Study) directed at testing the efficacy of the traditional Mediterranean diet (TMD) on the primary prevention of coronary heart disease, were assigned to a low-fat diet (n = 121) or one of 2 TMDs (TMD + virgin olive oil or TMD + nuts). The TMD participants received nutritional education and either free virgin olive oil for all the family (1 L/wk) or free nuts (30 g/d). Diets were ad libitum. Changes in oxidative stress markers were evaluated at 3 months. RESULTS After the 3-month interventions, mean (95% confidence intervals) oxidized low-density lipoprotein (LDL) levels decreased in the TMD + virgin olive oil (-10.6 U/L [-14.2 to -6.1]) and TMD + nuts (-7.3 U/L [-11.2 to -3.3]) groups, without changes in the low-fat diet group (-2.9 U/L [-7.3 to 1.5]). Change in oxidized LDL levels in the TMD + virgin olive oil group reached significance vs that of the low-fat group (P = .02). Malondialdehyde changes in mononuclear cells paralleled those of oxidized LDL. No changes in serum glutathione peroxidase activity were observed. CONCLUSIONS Individuals at high cardiovascular risk who improved their diet toward a TMD pattern showed significant reductions in cellular lipid levels and LDL oxidation. Results provide further evidence to recommend the TMD as a useful tool against risk factors for CHD. Trial Registration isrctn.org Identifier: ISRCTN35739639.

Urinary concentrations of phthalates and phenols in a population of Spanish pregnant women and children

BACKGROUND Phthalate and phenol exposure is prevalent among the general population and of potential concern for pregnant women and children because of their suspected susceptibility to endocrine effects. OBJECTIVES To evaluate the extent of exposure to several phthalates and phenols in a sample of Spanish pregnant women - according to their individual characteristics (age, social class, education, and body mass index) - and children who participated in the INMA - Infancia y Medio Ambiente (Environment and Childhood) project. METHODS One spot urine sample was taken during the third trimester of pregnancy from 120 pregnant women and from 30 4-year old children belonging to 5 Spanish birth cohorts, and analyzed for 11 phthalate metabolites and 9 phenols. RESULTS Three metabolites of di(2-ethylhexyl) phthalate, mono-2-ethyl-5-carboxypentyl phthalate, mono-2-ethyl-5-hydroxyhexyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate; two metabolites of dibutyl phthalates, mono-isobutyl phthalate and mono-n-butyl phthalate; monoethyl phthalate (MEP), the main metabolite of diethyl phthalate; and two phenols, methyl paraben (M-PB) and 2,5-dichlorophenol were detected in the urine samples of all women. The highest urinary concentrations were for MEP and M-PB. Urinary concentrations of all phthalate metabolites and of 2,4-dichlorophenol, 2,5-dichlorophenol, and bisphenol A were lower in the pregnant women than in the children. Among women, a positive relationship with social class and education was shown for most of the phthalate metabolites and phenols. Almost all phthalate metabolites varied by region even after adjusting for social class and education. CONCLUSIONS Phthalate and phenol exposures are prevalent in a group of pregnant women and young children, two susceptible populations, and these exposures might be positively related to social class.

Birth weight and prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE): A meta-analysis within 12 European birth cohorts

Objectives: Exposure to high concentrations of persistent organochlorines may cause fetal toxicity, but the evidence at low exposure levels is limited. Large studies with substantial exposure contrasts and appropriate exposure assessment are warranted. Within the framework of the EU (European Union) ENRIECO (ENvironmental Health RIsks in European Birth Cohorts) and EU OBELIX (OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life) projects, we examined the hypothesis that the combination of polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) adversely affects birth weight. Methods: We used maternal and cord blood and breast milk samples of 7,990 women enrolled in 15 study populations from 12 European birth cohorts from 1990 through 2008. Using identical variable definitions, we performed for each cohort linear regression of birth weight on estimates of cord serum concentration of PCB-153 and p,p´-DDE adjusted for gestational age and a priori selected covariates. We obtained summary estimates by meta-analysis and performed analyses of interactions. Results: The median concentration of cord serum PCB-153 was 140 ng/L (range of cohort medians 20–484 ng/L) and that of p,p´-DDE was 528 ng/L (range of cohort medians 50–1,208 ng/L). Birth weight decreased with increasing cord serum concentration of PCB-153 after adjustment for potential confounders in 12 of 15 study populations. The meta-analysis including all cohorts indicated a birth weight decline of 150 g [95% confidence interval (CI): –250, –50 g] per 1-µg/L increase in PCB-153, an exposure contrast that is close to the range of exposures across the cohorts. A 1-µg/L increase in p,p´-DDE was associated with a 7-g decrease in birth weight (95% CI: –18, 4 g). Conclusions: The findings suggest that low-level exposure to PCB (or correlated exposures) impairs fetal growth, but that exposure to p,p´-DDE does not. The study adds to mounting evidence that low-level exposure to PCBs is inversely associated with fetal growth.

Prenatal Organochlorine Compound Exposure, Rapid Weight Gain, and Overweight in Infancy

Background Although it has been hypothesized that fetal exposure to endocrine-disrupting chemicals may increase obesity risk, empirical data are limited, and it is uncertain how early in life any effects may begin. Objectives We explored whether prenatal exposure to several organochlorine compounds (OCs) is associated with rapid growth in the first 6 months of life and body mass index (BMI) later in infancy. Methods Data come from the INMA (Infancia y Medio-Ambiente) Child and Environment birth cohort in Spain, which recruited 657 women in early pregnancy. Rapid growth during the first 6 months was defined as a change in weight-for-age z-scores > 0.67, and elevated BMI at 14 months, as a z-score ≥ the 85th percentile. Generalized linear models were used to estimate the risk of rapid growth or elevated BMI associated with 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), hexachlorobenzene, β-hexachlorohexane, and polychlorinated biphenyls in first-trimester maternal serum. Results After multivariable adjustment including other OCs, DDE exposure above the first quartile was associated with doubling of the risk of rapid growth among children of normal-weight (BMI < 25 kg/m2), but not overweight, mothers. DDE was also associated with elevated BMI at 14 months (relative risk per unit increase in log DDE = 1.50; 95% confidence interval, 1.11–2.03). Other OCs were not associated with rapid growth or elevated BMI after adjustment. Conclusions In this study we found prenatal DDE exposure to be associated with rapid weight gain in the first 6 months and elevated BMI later in infancy, among infants of normal-weight mothers. More research exploring the potential role of chemical exposures in early-onset obesity is needed.

Association between GIS-based exposure to urban air pollution during pregnancy and birth weight in the INMA Sabadell Cohort

Background There is growing evidence that traffic-related air pollution reduces birth weight. Improving exposure assessment is a key issue to advance in this research area. Objective We investigated the effect of prenatal exposure to traffic-related air pollution via geographic information system (GIS) models on birth weight in 570 newborns from the INMA (Environment and Childhood) Sabadell cohort. Methods We estimated pregnancy and trimester-specific exposures to nitrogen dioxide and aromatic hydrocarbons [benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX)] by using temporally adjusted land-use regression (LUR) models. We built models for NO2 and BTEX using four and three 1-week measurement campaigns, respectively, at 57 locations. We assessed the relationship between prenatal air pollution exposure and birth weight with linear regression models. We performed sensitivity analyses considering time spent at home and time spent in nonresidential outdoor environments during pregnancy. Results In the overall cohort, neither NO2 nor BTEX exposure was significantly associated with birth weight in any of the exposure periods. When considering only women who spent < 2 hr/day in nonresidential outdoor environments, the estimated reductions in birth weight associated with an interquartile range increase in BTEX exposure levels were 77 g [95% confidence interval (CI), 7–146 g] and 102 g (95% CI, 28–176 g) for exposures during the whole pregnancy and the second trimester, respectively. The effects of NO2 exposure were less clear in this subset. Conclusions The association of BTEX with reduced birth weight underscores the negative role of vehicle exhaust pollutants in reproductive health. Time–activity patterns during pregnancy complement GIS-based models in exposure assessment.

Prenatal exposure to residential air pollution and infant mental development: modulation by antioxidants and detoxification factors.

Background: Air pollution effects on children’s neurodevelopment have recently been suggested to occur most likely through the oxidative stress pathway. Objective: We aimed to assess whether prenatal exposure to residential air pollution is associated with impaired infant mental development, and whether antioxidant/detoxification factors modulate this association. Methods: In the Spanish INfancia y Medio Ambiente (INMA; Environment and Childhood) Project, 2,644 pregnant women were recruited during their first trimester. Nitrogen dioxide (NO2) and benzene were measured with passive samplers covering the study areas. Land use regression models were developed for each pollutant to predict average outdoor air pollution levels for the entire pregnancy at each residential address. Maternal diet was obtained at first trimester through a validated food frequency questionnaire. Around 14 months, infant mental development was assessed using Bayley Scales of Infant Development. Results: Among the 1,889 children included in the analysis, mean exposure during pregnancy was 29.0 μg/m3 for NO2 and 1.5 μg/m3 for benzene. Exposure to NO2 and benzene showed an inverse association with mental development, although not statistically significant, after adjusting for potential confounders [β (95% confidence interval) = –0.95 (–3.90, 1.89) and –1.57 (–3.69, 0.56), respectively, for a doubling of each compound]. Stronger inverse associations were estimated for both pollutants among infants whose mothers reported low intakes of fruits/vegetables during pregnancy [–4.13 (–7.06, –1.21) and –4.37 (–6.89, –1.86) for NO2 and benzene, respectively], with little evidence of associations in the high-intake group (interaction p-values of 0.073 and 0.047). Inverse associations were also stronger in non-breast-fed infants and infants with low maternal vitamin D, but effect estimates and interactions were not significant. Conclusions: Our findings suggest that prenatal exposure to residential air pollutants may adversely affect infant mental development, but potential effects may be limited to infants whose mothers report low antioxidant intakes.

Genetic Variants of the FADS Gene Cluster and ELOVL Gene Family, Colostrums LC-PUFA Levels, Breastfeeding, and Child Cognition

Introduction Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs), but controversy persists. Genetic variation in fatty acid desaturase (FADS) and elongase (ELOVL) enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1) to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2) to analyze whether these maternal variants are related to child cognition; and 3) to assess whether childrens variants modify breastfeeding effects on cognition. Methods Data come from two population-based birth cohorts (n = 400 mother-child pairs from INMA-Sabadell; and n = 340 children from INMA-Menorca). LC-PUFAs were measured in 270 colostrum samples from INMA-Sabadell. Tag SNPs were genotyped both in mothers and children (13 in the FADS cluster, 6 in ELOVL2, and 7 in ELOVL5). Child cognition was assessed at 14 mo and 4 y using the Bayley Scales of Infant Development and the McCarthy Scales of Childrens Abilities, respectively. Results Children of mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis), higher FADS2 activity (regulating DHA synthesis), and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 mo (3.5 to 5.3 points). Not being breastfed conferred an 8- to 9-point disadvantage in cognition among children GG homozygote for rs174468 (low FADS1 activity) but not among those with the A allele. Moreover, not being breastfed resulted in a disadvantage in cognition (5 to 8 points) among children CC homozygote for rs2397142 (low ELOVL5 activity), but not among those carrying the G allele. Conclusion Genetically determined maternal supplies of LC-PUFAs during pregnancy and lactation appear to be crucial for child cognition. Breastfeeding effects on cognition are modified by child genetic variation in fatty acid desaturase and elongase enzymes.

Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P < 1.67 × 10(-8)) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased body mass index, reduced pubertal growth and earlier puberty. Whereas epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall, this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty and childhood obesity and provides new information to pinpoint processes linking these traits.

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.