Prenatal earthquake stress exposure in different gestational trimesters is associated with methylation changes in the glucocorticoid receptor gene (NR3C1) and long-term working memory in adulthood.

Prenatal stress exposure is thought to affect the long-term development of the foetal brain via the HPA axis and to change health outcomes in adulthood, including working memory (WM). The potential mechanism is that there is a critical period of brain development of the foetus, which is a result of selective adaptation to the external environment. The human glucocorticoid gene (NR3C1) is associated with memory and cognition. This study investigates the association between earthquake stress during pregnancy and CpG methylation of the NR3C1 exon 1 promoter and its influence on working memory in adulthood. DNA methylation analysis using bisulfite sequencing PCR was quantified in 176 subjects who were exposed or not exposed to intrauterine earthquake and were divided into three groups based on the pregnancy trimester. The Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) were used to assess working memory performance. The methylated NR3C1 exon 1 promoter of the prenatal earthquake exposure (PEE) group was significantly higher than that of the control group (CN). Analysis of subgroups indicated that the subjects in the second trimester of PEE group showed significantly higher methylation than those in the third trimester. Significantly low BVMT-R scores were detected in those who experienced prenatal earthquake in the second trimester of PEE group. Methylated CpG site 1 may play a critical role in contributing to lower BVMT-R scores in the second trimester in the PEE group, and may offer a potential epigenetic mechanism that links prenatal stress and long-term effects on working memory.