PC1051: Intrauterine Growth Restriction in a Mouse Model Is Associated with Dysregulation of Inflammatory Regulatory microrna-146a

Background: Intrauterine growth restriction (IUGR) is a common pregnancy complication associated with significant long-term sequala. Individuals with a history of IUGR are at increased risk of hypertension, cardiovascular disease, obesity, and type II diabetes mellitus. While the pathogenesis leading to IUGR is multifactorial, recent studies suggest a chronic inflammatory state associated with IUGR. In addition, many of the long-term sequala of IUGR are also associated with a chronic inflammatory state. MicroRNAs (miRs) are short non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting mRNA for degradation or suppressing mRNA translation. miR-146a has been associated with chronic inflammation in disease processes such as type II diabetes mellitus, Grave’s disease, and rheumatoid arthritis. We hypothesize that miR-146a, as well as its downstream effector proteins and cytokines, are dysregulated in an IUGR mouse model.

Methods: Pregnant mice were provided ad libitum access to food between E1-E8. From E9-E18, dams received either a 50% caloric restricted diet (IUGR) or continued ad libitum access (controls). Placentas were harvested at E18.5. RNA was extracted using a column-based extraction technique. Primers for miR146a as well as downstream mRNA targets were used to compare levels of gene expression between IUGR and control placentas. Statistical comparisons utilized student t-test with a p-value < 0.05 signifying significance.

Results: Ten placentas in the IUGR group were compared to ten placentas in the control group. Relative gene expression of the anti-inflammatory miR-146a was downregulated within placentas affected by IUGR. Gene expression of the downstream regulatory protein, nuclear factor kappa B (NFkB), was upregulation. In addition, gene expression of pro-inflammatory cytokines modulated by NFkB, Interleukin-6 (IL-6), and Interleukin-8 (IL-8), were also upregulated within IUGR placentas (Figures 1 and 2).

Conclusion: IUGR has been associated with a chronic inflammatory state and our caloric restricted mouse model of IUGR recapitulates this inflammatory state evident by increased gene expression of NFkB, IL-6, and IL-8. As these mediators are also elevated in chronic disease processes such as cardiovascular disease and type II diabetes mellitus, our findings suggests that inflammatory pathways associated with IUGR may be the same ones associated with sequela of IUGR. The observation that miR-146a is downregulated in IUGR suggests microRNA dysregulation may play a central role in the inflammatory pathogenesis of IUGR. Therapeutic options to mitigate this inflammatory milieu may include transplacental supplementation of miR-146a with the goal of improving IUGR outcomes as well as subsequent long term complications.