In Utero Heat Stress Alters the Offspring Epigenome

A L Skibiel,B M Ahmed,G E Dahl,J Laporta,R Amorín,F Peñagaricano

doi:10.1038/s41598-018-32975-1

Abstract

Exposure to intrauterine heat stress during late gestation affects offspring performance into adulthood. However, underlying mechanistic links between thermal insult in fetal life and postnatal outcomes are not completely understood. We examined morphology, DNA methylation, and gene expression of liver and mammary gland for bull calves and heifers that were gestated under maternal conditions of heat stress or cooling (i.e. in utero heat stressed vs. in utero cooled calves). Mammary tissue was harvested from dairy heifers during their first lactation and liver from bull calves at birth. The liver of in utero heat stressed bull calves contained more cells and the mammary glands of in utero heat stressed heifers were comprised of smaller alveoli. We identified more than 1,500 CpG sites differently methylated between maternal treatment groups. These CpGs were associated with approximately 400 genes, which play a role in processes, such as development, innate immune defense, cell signaling, and transcription and translation. We also identified over 100 differentially expressed genes in the mammary gland with similar functions. Interestingly, fifty differentially methylated genes were shared by both bull calf liver and heifer mammary gland. Intrauterine heat stress alters the methylation profile of liver and mammary DNA and programs their morphology in postnatal life, which may contribute to the poorer performance of in utero heat stressed calves.

Highlights

Life experiences can program physiological function and health and disease outcomes later in life[1,2]
The mammary glands of in utero heat stressed heifers (IUHT-H) and in utero cooled heifers (IUCL-H) had a similar number of alveoli (t = 0.95, df = 5, P = 0.38), but the area of IUCL-H alveoli was significantly larger than IUHT-H (t = 2.61, df = 5, P = 0.05; Fig. 1C–E)
We identified 15,366 genes expressed in the mammary gland of heifers, 117 of which were differentially expressed between IUHT-H and IUCL-H (P ≤ 0.01; Supplementary Table S4)

Summary

Introduction

Life experiences can program physiological function and health and disease outcomes later in life[1,2]. The mechanisms through which in utero heat stress in late gestation affects postnatal liver and mammary function have yet to be elucidated, but could be attributed, in part, to impairment of tissue growth during the organ maturation stage of fetal development. Development, exposure of multiparous dry cows to heat stress depressed mammary epithelial cell proliferation, potentially reducing the total number of cells in the mammary gland capable of producing milk[18]. Our hypothesis is that in utero heat stress drives changes in phenotype by altered DNA methylation of key regulatory gene pathways in the liver and mammary gland. Specific objectives of this study were to, 1) examine effects of fetal exposure to intrauterine heat stress during late gestation on the postnatal mammary gland and liver tissue microstructure and, 2) to characterize changes in DNA methylation and gene expression that may explain the observed phenotypic outcomes

Methods

Results

Discussion

Conclusion