Associations between prenatal phthalate exposure and childhood epigenetic age acceleration

BackgroundPhthalates, a group of pervasive endocrine-disrupting chemicals found in plastics and personal care products, have been associated with a wide range of developmental and health outcomes. However, their impact on biomarkers of aging has not been characterized. We tested associations between prenatal exposure to 11 phthalate metabolites on epigenetic aging in children at birth, 7, 9, and 14 years of age. We hypothesized that prenatal phthalate exposure will be associated with epigenetic age acceleration measures at birth and in early childhood, with patterns dependent on sex and timing of DNAm measurement.MethodsAmong 385 mother-child pairs from the CHAMACOS cohort, we measured DNAm at birth, 7, 9, and 14 years of age, and utilized adjusted linear regression to assess the association between prenatal phthalate exposure and Bohlin's Gestational Age Acceleration (GAA) at birth and Intrinsic Epigenetic Age Acceleration (IEAA) throughout childhood. Additionally, quantile g-computation was utilized to assess the effect of the phthalate mixture on GAA at birth and IEAA throughout childhood.ResultsWe found a negative association between prenatal di (2-ethylhexyl) phthalate (DEHP) exposure and IEAA among males at age 7 (-0.62 years; 95% CI:-1.06 to -0.18), and a marginal negative association between the whole phthalate mixture and GAA among males at birth (-1.54 days, 95% CI: -2.79 to -0.28), while most other associations were nonsignificant.ConclusionsOur results suggest that prenatal exposure to certain phthalates is associated with epigenetic aging in children. Additionally, our findings suggest that the influence of prenatal exposures on epigenetic age may only manifest during specific periods of child development, and studies relying on DNAm measurements solely from cord blood or single time points may overlook potential relationships

Comparison of DNA methylation measurements from EPIC BeadChip and SeqCap targeted bisulphite sequencing in PON1 and nine additional candidate genes

Epigenome-wide association studies (EWAS) are widely implemented in epidemiology, and the Illumina HumanMethylationEPIC BeadChip (EPIC) DNA microarray is the most-used technology. Recently, next-generation sequencing (NGS)-based methods, which assess DNA methylation at single-base resolution, have become more affordable and technically feasible. While the content of microarray technology is fixed, NGS-based approaches, such as the Roche Nimblegen, SeqCap Epi Enrichment System (SeqCap), offer the flexibility of targeting most CpGs in a gene. With the current usage of microarrays and emerging NGS-based technologies, it is important to establish whether data generated from the two platforms are comparable. We harnessed 112 samples from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort study and compared DNA methylation between the EPIC microarray and SeqCap for PON1 and nine additional candidate genes, by evaluating epigenomic coverage and correlations. We conducted multivariable linear regression and principal component analyses to assess the ability of the EPIC array and SeqCap to detect biological differences in gene methylation by the PON1−108 single nucleotide polymorphism. We found an overall high concordance (r = 0.84) between SeqCap and EPIC DNA methylation, among highly methylated and minimally methylated regions. However, substantial disagreement was present between the two methods in moderately methylated regions, with SeqCap measurements exhibiting greater within-site variation. Additionally, SeqCap did not capture PON1 SNP associated differences in DNA methylation that were evident with the EPIC array. Our findings indicate that microarrays perform well for analysing DNA methylation in large cohort studies but with limited coverage

Characterizing the Modern Light Environment and its Influence on Circadian Rhythms

Humans have largely supplanted natural light cycles with a variety of artificial light sources and schedules misaligned with day-night cycles. Circadian disruption has been linked to a number of disease processes, but the extent of circadian disruption among the population is unknown. We measured light exposure and wrist temperature among residents of an urban area for a full week during each of the four seasons, as well as light illuminance in nearby outdoor locations. Daily light exposure was significantly lower for individuals, compared to outdoor light sensors, for all four seasons. There was also little seasonal variation in the realized photoperiod experienced by individuals, with the only significant difference between winter and summer. We tested the hypothesis that differential light exposure impacts circadian phase timing, detected via the wrist temperature rhythm. To determine the influence of light exposure on circadian rhythms, we modeled the impact of morning, afternoon, and nighttime light exposure on the timing of the midline-estimating statistic of rhythm (MESOR). We found that morning light exposure and nighttime light exposure had a significant but opposing impact on MESOR timing. Our results demonstrate that nighttime light can shift/alter circadian rhythms to delay the morning transition from nighttime to daytime physiology, while morning light can lead to earlier onset. Our results demonstrate that circadian shifts and disruptions may be a more regular occurrence in the general population than is currently recognized.Significance Statement: Disruption of circadian rhythms has been linked to various diseases, but the prevalence of circadian disruption among the general population is unknown. Light plays a pivotal role in entraining circadian rhythms to the 24-hour day. Humans have largely supplanted natural light cycles with electrical lighting and through time spent indoors. We have shown that individuals experience a disconnect from natural light cycles, with low daytime light exposure, high levels of light-at-night, and minimal seasonal variation in light exposure. We identified measurable changes in the timing of wrist temperature rhythms as a function of differential light exposure during the morning and nighttime hours. Our findings suggest that circadian shifts, and potentially disruption, may be common in the general population

Maternal age is related to offspring DNA methylation: a meta-analysis of results from the PACE consortium

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9,500 newborns and 2,000 children (5-10 years old) from the Pregnancy And Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR<0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B at which higher DNAm was associated with greater maternal age (PFDR=6.92x10-8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p<0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR<0.05) and nominally in childhood (p<0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health

Maternal age is related to offspring DNA methylation : a meta-analysis of results from the pace consortium

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health