Prenatal exposure to TCDD and atopic conditions in the Seveso second generation: a prospective cohort study.

Background2,3,7,8-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.MethodsIndividual-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.ResultsA 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.ConclusionsOur 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

Associations of PON1 and genetic ancestry with obesity in early childhood.

Obesity in children has become an epidemic in the U.S. and is particularly prominent in minority populations such as Mexican-Americans. In addition to physical activity and diet, genetics also plays a role in obesity etiology. A few studies in adults and adolescents suggest a link between obesity and paraoxonase 1 (PON1), a multifunctional enzyme that can metabolize organophosphate pesticides and also has antioxidant properties. We determined PON1192 genotype and arylesterase levels (ARYase, measure of PON1 enzyme quantity), to characterize the relationship between PON1 and obesity in young Mexican-American children (n = 373) living in an agricultural community in California. Since PON1 polymorphisms and obesity both vary between ethnic groups, we estimated proportional genetic ancestry using 106 ancestral informative markers (AIMs). Among children, PON1192 allele frequencies were 0.5 for both alleles, and the prevalence of obesity was high (15% and 33% at ages two and five, respectively). The average proportion of European, African, and Native American ancestry was 0.40, 0.09, and 0.51, yet there was wide inter-individual variation. We found a significantly higher odds of obesity (9.3 and 2.5- fold) in PON1192QQ children compared to PON1192RR children at ages two and five, respectively. Similar relationships were seen with BMI Z-scores at age two and waist circumference at age five. After adjusting for genetic ancestry in models of PON1 and BMI Z-score, effect estimates for PON1192 genotype changed 15% and 9% among two and five year old children, respectively, providing evidence of genetic confounding by population stratification. However even after adjustment for genetic ancestry, the trend of increased BMI Z-scores with increased number of PON1192 Q alleles remained. Our findings suggest that PON1 may play a role in obesity independent of genetic ancestry and that studies of PON1 and health outcomes, especially in admixed populations, should account for differences due to population stratification

Will buffer zones around schools in agricultural areas be adequate to protect children from the potential adverse effects of pesticide exposure?

California has proposed limiting agricultural pesticide use within 0.4 km of schools and childcare facilities. However, the 0.4-km buffer may not be appropriate for all pesticides because of differing toxicities, fate, and application methods. Living near pesticide use has been associated with poorer birth outcomes, neurodevelopment, and respiratory function in children. More research about exposures in schools, childcare facilities, and homes is needed. Despite incomplete science, this regulation is an important step to reduce potential exposures to children. The most vulnerable exposure period may be in utero, and future regulations should also aim to reduce exposures to pregnant women

DNA methylation and socioeconomic status in a Mexican-American birth cohort.

Background: Maternal social environmental stressors during pregnancy are associated with adverse birth and child developmental outcomes, and epigenetics has been proposed as a possible mechanism for such relationships. Methods: In a Mexican-American birth cohort of 241 maternal-infant pairs, cord blood samples were measured for repeat element DNA methylation (LINE-1 and Alu). Linear mixed effects regression was used to model associations between indicators of the social environment (low household income and education, neighborhood-level characteristics) and repeat element methylation. Results from a dietary questionnaire were also used to assess the interaction between maternal diet quality and the social environment on markers of repeat element DNA methylation. Results: After adjusting for confounders, living in the most impoverished neighborhoods was associated with higher cord blood LINE-1 methylation (β = 0.78, 95%CI 0.06, 1.50, p = 0.03). No other neighborhood-, household-, or individual-level socioeconomic indicators were significantly associated with repeat element methylation. We observed a statistical trend showing that positive association between neighborhood poverty and LINE-1 methylation was strongest in cord blood of infants whose mothers reported better diet quality during pregnancy (pinteraction = 0.12). Conclusion: Our findings indicate a small yet unexpected positive association between neighborhood-level poverty during pregnancy and methylation of repetitive element DNA in infant cord blood and that this association is possibly modified by diet quality during pregnancy. However, our null findings for other adverse SES indicators do not provide strong evidence for an adverse association between early-life socioeconomic environment and repeat element DNA methylation in infants

Sex differences in DNA methylation assessed by 450 K BeadChip in newborns.

BackgroundDNA methylation is an important epigenetic mark that can potentially link early life exposures to adverse health outcomes later in life. Host factors like sex and age strongly influence biological variation of DNA methylation, but characterization of these relationships is still limited, particularly in young children.MethodsIn a sample of 111 Mexican-American subjects (58 girls , 53 boys), we interrogated DNA methylation differences by sex at birth using the 450 K BeadChip in umbilical cord blood specimens, adjusting for cell composition.ResultsWe observed that ~3% of CpG sites were differentially methylated between girls and boys at birth (FDR P < 0.05). Of those CpGs, 3031 were located on autosomes, and 82.8% of those were hypermethylated in girls compared to boys. Beyond individual CpGs, we found 3604 sex-associated differentially methylated regions (DMRs) where the majority (75.8%) had higher methylation in girls. Using pathway analysis, we found that sex-associated autosomal CpGs were significantly enriched for gene ontology terms related to nervous system development and behavior. Among hits in our study, 35.9% had been previously reported as sex-associated CpG sites in other published human studies. Further, for replicated hits, the direction of the association with methylation was highly concordant (98.5-100%) with previous studies.ConclusionsTo our knowledge, this is the first reported epigenome-wide analysis by sex at birth that examined DMRs and adjusted for confounding by cell composition. We confirmed previously reported trends that methylation profiles are sex-specific even in autosomal genes, and also identified novel sex-associated CpGs in our methylome-wide analysis immediately after birth, a critical yet relatively unstudied developmental window

Pregnancy lipidomic profiles and DNA methylation in newborns from the CHAMACOS cohort.

Lipids play a role in many biological functions and the newly emerging field of lipidomics aims to characterize the varying classes of lipid molecules present in biological specimens. Animal models have shown associations between maternal dietary supplementation with fatty acids during pregnancy and epigenetic changes in their offspring, demonstrating a mechanism through which prenatal environment can affect outcomes in children; however, data on maternal lipid metabolite levels during pregnancy and newborn DNA methylation in humans are sparse. In this study, we assessed the relationship of maternal lipid metabolites measured in the blood from pregnant women with newborn DNA methylation profiles in the Center for the Health Assessment of Mothers and Children of Salinas cohort. Targeted metabolomics was performed by selected reaction monitoring liquid chromatography and triple quadrupole mass spectrometry to measure 92 metabolites in plasma samples of pregnant women at ∼26 weeks gestation. DNA methylation was assessed using the Infinium HumanMethylation 450K BeadChip adjusting for cord blood cell composition. We uncovered numerous false discovery rate significant associations between maternal metabolite levels, particularly phospholipid and lysolipid metabolites, and newborn methylation. The majority of the observed relationships were negative, suggesting that higher lipid metabolites during pregnancy are associated with lower methylation levels at genes related to fetal development. These results further elucidate the complex relationship between early life exposures, maternal lipid metabolites, and infant epigenetic status

A Modified Trier Social Stress Test for Vulnerable Mexican American Adolescents.

The Trier Social Stress Test (TSST) is a well validated and widely used social stressor that has been shown to induce a 2-4 fold increase in cortisol, the biological output produced by the Hypothalamic-Pituitary-Adrenal (HPA) axis in humans. While studies have explored how modifications to the TSST influence stress responsivity, few studies have created a modified TSST appropriate for vulnerable youth that elicits a significant cortisol stress response. Thus, the current study sought to modify or adjust the TSST in a culturally sensitive way for a vulnerable sample of 14 year-old adolescents. The present study took place within the context of a longitudinal birth cohort study of Mexican American families in California called the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). The CHAMACOS sample was optimal to test the effectiveness of a modified culturally appropriate TSST, as it is comprised of Mexican American youth, who are often excluded from research. These youths also have experienced significant early life adversity. Example modifications included timed prompts, alternative math tasks, use of same-ethnicity peers as confederates, debriefing immediately after the conclusion of the TSST, and using an unknown youth examiner to administer the debrief. Saliva samples were collected at baseline (after a resting phase), and then again at 15, 30, and 45 min post-TSST onset to assess cortisol concentration. A pilot study of 50 participants (50% female) have been analyzed for cortisol reaction to the TSST. Results confirmed that this modified version of the TSST was successful at eliciting a significant cortisol reaction, with a wide range of variability likely due to individual differences. Goals for modifications and ethnicity considerations are discussed. This study provides the foundation for future research to utilize a modified TSST with vulnerable youth