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Persistent epigenetic changes in adult daughters of older mothers.

ABSTRACT: Women of advanced maternal age account for an increasing proportion of live births in many developed countries across the globe. Offspring of older mothers are at an increased risk for a variety of subsequent health outcomes, including outcomes that do not manifest until childhood or adulthood. The molecular underpinnings of the association between maternal aging and offspring morbidity remain elusive. However, one possible mechanism is that maternal aging produces specific alterations in the offspring's epigenome in utero, and these epigenetic alterations persist into adulthood. We conducted an epigenome-wide association study (EWAS) of the effect of a mother's age on blood DNA methylation in 2,740 adult daughters using the Illumina Infinium HumanMethylation450 array. A false discovery rate (FDR) q-value threshold of 0.05 was used to identify differentially methylated CpG sites (dmCpGs). We identified 87 dmCpGs associated with increased maternal age. The majority (84%) of the dmCpGs had lower methylation in daughters of older mothers, with an average methylation difference of 0.6% per 5-year increase in mother's age. Thirteen genomic regions contained multiple dmCpGs. Most notably, nine dmCpGs were found in the promoter region of the gene LIM homeobox 8 (LHX8), which plays a pivotal role in female fertility. Other dmCpGs were found in genes associated with metabolically active brown fat, carcinogenesis, and neurodevelopmental disorders. We conclude that maternal age is associated with persistent epigenetic changes in daughters at genes that have intriguing links to health.

SUBMITTER: Moore AM

PROVIDER: S-EPMC6557560 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Persistent epigenetic changes in adult daughters of older mothers.

Moore Aaron M AM Xu Zongli Z Kolli Ramya T RT White Alexandra J AJ Sandler Dale P DP Taylor Jack A JA

Epigenetics 20190328 5

Women of advanced maternal age account for an increasing proportion of live births in many developed countries across the globe. Offspring of older mothers are at an increased risk for a variety of subsequent health outcomes, including outcomes that do not manifest until childhood or adulthood. The molecular underpinnings of the association between maternal aging and offspring morbidity remain elusive. However, one possible mechanism is that maternal aging produces specific alterations in the of ...[more]

PMID: 30879397

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Project description:Few studies to date have used the cancer diagnosis as a teachable moment to promote healthy behavior changes in survivors of cancer and their family members. Given the role of obesity in the primary and tertiary prevention of breast cancer, the authors explored the feasibility of a mother-daughter weight loss intervention.A randomized controlled trial of a mailed weight loss intervention was undertaken among 68 mother-daughter dyads (n = 136), each comprised of a survivor of breast cancer (AJCC stage 0-III) and her adult biological daughter. All women had body mass indices ? 25 kg/m(2) and underwent in-person assessments at baseline, 6 months, and 12 months, with accelerometry and exercise capacity performed on a subset of individuals. All women received a personalized workbook and 6 newsletters over a 1-year period that promoted weight loss; exercise; and a nutrient-rich, low-energy density diet. A total of 25 dyads received individually tailored instruction (individual), 25 dyads received team-tailored instruction (TEAM), and 18 dyads received standardized brochures (control).The trial met its accrual target, experienced 90% retention, and caused no serious adverse events. Significant differences in baseline to 12-month changes were observed between individual versus control mothers for body mass index, weight, and waist circumference (WC); significant differences also were observed in the WC of corresponding daughters (P <?.05). Significant differences were found between individual versus control and team versus control dyads for WC (P =?.0002 and .018, respectively), minutes per week of physical activity (P =?.031 and .036, respectively), and exercise capacity (P =?.047 for both).Significant improvements in lifestyle behaviors and health outcomes are possible with tailored print interventions directed toward survivors of cancer and their family members. For greater impact, more research is needed to expand this work beyond the mother-daughter dyad.

Project description:Study questionIs there an association between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and fecundability and infertility among Seveso women and their daughters?Summary answerTCDD exposure is associated with a decrease in fecundability and increased risk of infertility in women, as well as their daughters.What is known alreadyIn animal studies, maternal exposure to TCDD is associated with decreased fertility in offspring. Effects of TCDD are mediated by activation of the aryl hydrocarbon receptor (AHR) pathway.Study design, size, durationThe Seveso Women's Health Study (SWHS) has followed 981 women exposed to TCDD in a 1976 accident since 1996. In 2014, we initiated the Seveso Second Generation Study to follow-up their children.Participants/materials, setting, methodsWe obtained information on pregnancy history including time of trying to conceive from SWHS women and their daughters who were 18 years or older. We considered TCDD exposure as initial 1976 serum TCDD concentration and estimated TCDD at pregnancy. We examined relationships of TCDD exposure with time to pregnancy (TTP, the monthly probability of conception within the first 12 months of trying) and infertility (≥12 months of trying to conceive). We also assessed contributions of polymorphisms in the AHR pathway via genetic risk score.Main results and the role of chanceAmong SWHS women (n = 446), median TTP was 3 months and 18% reported taking ≥12 months to conceive. Initial 1976 TCDD (log10) was associated with longer TTP (adjusted fecundability odds ratio = 0.82; 95% CI 0.68-0.98) and increased risk of infertility (adjusted relative risk = 1.35; 95% CI 1.01-1.79). TCDD at pregnancy yielded similar associations. Among SWHS daughters (n = 66), median TTP was 2 months and 11% reported taking ≥12 months to conceive. Daughters showed similar, but non-significant, associations with maternal TCDD exposure.Limitations, reasons for cautionA limitation of this study is time to pregnancy was reported retrospectively, although previous studies have found women are able to recall time to conception with a high degree of accuracy many years after the fact. The number of SWHS daughters who had a live birth was small and we were unable to examine fecundability of SWHS sons.Wider implications of the findingsConsistent with previous findings in animal studies, our study found that TCDD exposure may be associated with decreased fertility in Seveso mothers and potentially in their daughters exposed in utero. There may be susceptible genetic subgroups. The literature has largely considered the genetics of the AHR pathway in the context of male fertility but not female fertility, despite strong biological plausibility. These findings should be replicated in larger populations and of different ancestry. Future studies in Seveso should examine the sons and the grandchildren of exposed mothers given the animal literature suggesting potential heritable epigenetic effects.Study funding/competing interest(s)This study was supported by grant numbers F06 TW02075-01 from the National Institutes of Health, R01 ES07171 and 2P30-ESO01896-17 from the National Institute of Environmental Health Sciences, R82471 from the U.S. Environmental Protection Agency and #2896 from Regione Lombardia and Fondazione Lombardia Ambiente, Milan, Italy. J.A. was supported by F31ES026488 from the National Institutes of Health. The authors declare they have no actual or potential competing financial interests.Trial registration numberN/A.

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Persistent epigenetic changes in adult daughters of older mothers.

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Persistent epigenetic changes in adult daughters of older mothers.

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