Regulation of birthweight by placenta-derived miRNAs: evidence from an arsenic-exposed birth cohort in Bangladesh

Abstract

Altered expression of microRNAs (miRNAs) is implicated in fetal growth. However, the mechanisms by which placenta-derived miRNAs regulate birthweight are not well understood. In Phase 1, we compared the expression of 754 miRNAs in the placenta of mothers from two extreme birthweight groups (0.8-2.2 kg vs. 3.3-3.9 kg, n = 77 each) selected from an arsenic-exposed Bangladeshi birth cohort (n = 1,141). We identified 49 miRNAs associated with the extreme birthweight groups and/or gestational age in Phase 1, which were further analyzed in Phase 2 among 364 randomly selected mother-infant pairs. Gestational age was determined by ultrasound. Causal mediation analysis was used to estimate the effect of miRNAs on birthweight considering gestational age a mediator, adjusting for core blood arsenic and other risk factors. miR-1290, miR-195, and let-7g showed significant inverse associations with gestational age, while miR-328 showed significant positive association [false discovery rate (FDR) <0.05]. Via changing gestational age, miR-1290, miR-195, and miR-27a showed significant inverse associations with birthweight, while miR-328 and miR-324-5p showed significant positive associations (FDR <0.05). The effect of miRNAs on birthweight varied by gestational age (for miR-1290, miR-195, miR-328) and in utero arsenic exposure (for miR-1290): stronger effect was observed among infants delivered early in gestation or exposed to higher concentrations of arsenic in cord blood. Gene enrichment analysis with in silico predicted targets identified cell proliferation, inflammation, apoptosis, insulin, and IGF family signaling cascades associated with these miRNAs. Future studies are warranted to replicate these findings and assess these miRNAs as early biomarkers of fetal growth.

High-throughput miRNA-sequencing of the human placenta: expression throughout gestation

“…10–12 The complexities of normal placental development are under the control of various epigenetic modifications that may be altered, ultimately leading to abnormal placentation and adverse outcomes. 13,14…”

A burst of regulatory and protein innovation at the origin of placental mammals drove the emergence of placenta and underpins divergent early pregnancy strategies in modern mammals

“…Others have been implicated in pathophysiological pregnancies, e.g. mir-185, mir-188, mir-423 and mir-542 [15][16][17] have been implicated in preeclampsia, mir-127 10 has been associated with placentomegaly, mir-324 is associated with LGA pregnancies 18 , mir-331 is associated with placenta from intra-amniotic infection 19 , and mir-505 can be associated with preterm birth 20 . Collectively all 13 members of the core miRNA toolkit have been implicated in critical roles in placental mammal pregnancies.…”

Air pollution-induced placental alterations: an interplay of oxidative stress, epigenetics, and the aging phenotype?

“…Until now, most studies focused on chemical exposures including cadmium [57], phthalates [58], arsenic [59], and endocrine disrupting chemicals [60] in association with placental miRNAs. Moreover, multiple studies confirm a role for miRNAs in the response to air pollution exposure in adults [61–63].…”