Mediating role of whole epigenome DNA methylation signatures in the association between copper and SGA.

BACKGROUND

Trace element Cu is associated with the risk of small for gestational age infants, but its underlying mechanism is still unclear. This study aims to explore the possible mechanism of Cu induced SGA from the perspective of DNA methylation.

METHODS

We performed epigenome-wide DNA methylation analysis of umbilical cord blood from small for gestational age infants (SGA, n = 35) and appropriate for gestational age infants (AGA, n = 61) at birth to explore SGA related epigenome-wide DNA methylation sites. Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) was used to detect their umbilical cord blood Cu levels. Multiple linear regression models were used to explore the effect of Cu on SGA-related DNA methylation sites, and mediation analysis was further applied to explore the potential mediating factors of DNA methylation. The false discovery rate（FDR）was used for multiple comparisons.

RESULTS

Compared with AGA (452 ng/mL), SGA infants (532 ng/mL) had higher umbilical cord blood Cu concentration (P < 0.05). Seven Cu-related CpG sites were identified from epigenome-wide DNA methylation association analysis with SGA. Among them, a significant mediation effect of FLT3（cg10763141） methylation level in the association between high exposure level of Cu and SGA (P = 0.024). The mediation analysis showed a mediation proportion of 44.7 %.

CONCLUSIONS

Consistent with previous findings, we found that Cu was associated with the risk of SGA, and seven differentially methylated sites significantly associated with Cu were observed in the epigenome wide DNA methylation association study of SGA. FLT3（cg10763141）mediates the correlation between Cu and SGA. Cu may increase the risk of SGA by altering DNA methylation in certain genes (particularly FLT3). Our study provides new clues for the mechanism of SGA.