Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
Hum Reprod. 2022 Aug 25;37(9):2063-2074. doi: 10.1093/humrep/deac147.
Is the use of ART, a proxy for infertility, associated with epigenetic age acceleration?
The epigenetic age acceleration measured by Dunedin Pace of Aging methylation (DunedinPoAm) differed significantly between non-ART and ART mothers.
Among mothers who used ART, epigenetic age acceleration may be associated with low oocyte yield and poor ovarian response. However, the difference in epigenetic age acceleration between non-ART and ART mothers (or even fathers) has not been examined.
STUDY DESIGN, SIZE, DURATION: The Norwegian Mother, Father and Child Cohort Study (MoBa) recruited pregnant women and their partners across Norway at around 18 gestational weeks between 1999 and 2008. Approximately 95 000 mothers, 75 000 fathers and 114 000 children were included. Peripheral blood samples were taken from mothers and fathers at ultrasound appointments or from mothers at childbirth, and umbilical cord blood samples were collected from the newborns at birth.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Among the MoBa participants, we selected 1000 couples who conceived by coitus and 894 couples who conceived by IVF (n = 525) or ICSI (n = 369). We measured their DNA methylation (DNAm) levels using the Illumina MethylationEPIC array and calculated epigenetic age acceleration. A linear mixed model was used to examine the differences in five different epigenetic age accelerations between non-ART and ART parents.
We found a significant difference in the epigenetic age acceleration calculated by DunedinPoAm between IVF and non-ART mothers (0.021 years, P-value = 2.89E-06) after adjustment for potential confounders. Further, we detected elevated DunedinPoAm in mothers with tubal factor infertility (0.030 years, P-value = 1.34E-05), ovulation factor (0.023 years, P-value = 0.0018) and unexplained infertility (0.023 years, P-value = 1.39E-04) compared with non-ART mothers. No differences in epigenetic age accelerations between non-ART and ICSI fathers were found. DunedinPoAm also showed stronger associations with smoking, education and parity than the other four epigenetic age accelerations.
LIMITATIONS, REASONS FOR CAUTION: We were not able to determine the directionality of the causal pathway between the epigenetic age accelerations and infertility. Since parents' peripheral blood samples were collected after conception, we cannot rule out the possibility that the epigenetic profile of ART mothers was influenced by the ART treatment. Hence, the results should be interpreted with caution, and our results might not be generalizable to non-pregnant women.
A plausible biological mechanism behind the reported association is that IVF mothers could be closer to menopause than non-ART mothers. The pace of decline of the ovarian reserve that eventually leads to menopause varies between females yet, in general, accelerates after the age of 30, and some studies show an increased risk of infertility in females with low ovarian reserve.
STUDY FUNDING/COMPETING INTEREST(S): This study was partly funded by the Research Council of Norway (Women's fertility, project no. 320656) and through its Centres of Excellence Funding Scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement number 947684). The authors declare no conflict of interest.
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辅助生殖技术（ART）的使用是否与表观遗传年龄加速有关？
通过 Dunedin 衰老速度甲基化（DunedinPoAm）测量的表观遗传年龄加速在非 ART 母亲和 ART 母亲之间有显著差异。
在使用 ART 的母亲中，低卵母细胞产量和卵巢反应不良可能与表观遗传年龄加速有关。然而，非 ART 母亲和 ART 母亲（甚至父亲）之间的表观遗传年龄加速差异尚未被研究。
研究设计、规模、持续时间：挪威母亲、父亲和儿童队列研究（MoBa）在 1999 年至 2008 年期间在挪威各地招募了大约 18 孕周的孕妇及其伴侣。大约有 95000 名母亲、75000 名父亲和 114000 名儿童被纳入研究。母亲和父亲在超声检查时或母亲在分娩时抽取外周血样本，新生儿在出生时抽取脐带血样本。
参与者/材料、设置、方法：在 MoBa 参与者中，我们选择了 1000 对通过性交受孕的夫妇和 894 对通过体外受精（IVF）或卵胞浆内单精子注射（ICSI）受孕的夫妇（n=525）。我们使用 Illumina MethylationEPIC 阵列测量他们的 DNA 甲基化（DNAm）水平，并计算表观遗传年龄加速。线性混合模型用于检查非 ART 父母和 ART 父母之间五种不同的表观遗传年龄加速之间的差异。
在调整了潜在的混杂因素后，我们发现 IVF 母亲和非 ART 母亲之间通过 DunedinPoAm 计算的表观遗传年龄加速有显著差异（0.021 岁，P 值=2.89E-06）。此外，我们发现输卵管因素不孕（0.030 岁，P 值=1.34E-05）、排卵因素（0.023 岁，P 值=0.0018）和不明原因不孕（0.023 岁，P 值=1.39E-04）的母亲的 DunedinPoAm 升高，与非 ART 母亲相比。我们没有发现非 ART 父亲和 ICSI 父亲之间的表观遗传年龄加速有差异。DunedinPoAm 与吸烟、教育和产次的关联也比其他四种表观遗传年龄加速更强。
局限性、谨慎的原因：我们无法确定表观遗传年龄加速和不孕之间的因果关系的方向。由于父母的外周血样本是在受孕后采集的，我们不能排除 ART 母亲的表观遗传特征受到 ART 治疗影响的可能性。因此，结果应谨慎解读，我们的结果可能不适用于未怀孕的女性。
报道的关联背后的一个合理的生物学机制是，IVF 母亲可能比非 ART 母亲更接近更年期。最终导致更年期的卵巢储备下降的速度在女性之间有所不同，但通常在 30 岁后加速，一些研究表明，卵巢储备低的女性不孕风险增加。
研究资金/竞争利益：这项研究部分由挪威研究理事会（妇女生育能力，项目编号 320656）资助，并通过其卓越研究中心资助计划（项目编号 262700）提供资金。M.C.M. 收到了欧洲研究理事会（ERC）的资助（欧盟地平线 2020 研究和创新计划的资助协议号 947684）。作者声明没有利益冲突。
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