Increased Concentrations of Insulin-Like Growth Factor Binding Protein (IGFBP)-2, IGFBP-3, and IGFBP-4 Are Associated With Fetal Mortality in Pregnant Cows.

Kirsten Mense,Yette Brockelmann,Ralf Bortfeldt,Elisa Wirthgen,Sarah Peter,Markus Jung,Julia Heidekorn-Dettmer,Christine Höflich,Andreas Hoeflich,Marion Schmicke

doi:10.3389/fendo.2018.00310

Abstract

Insulin-like growth factors (IGFs) play a critical role in fetal growth, and components of the IGF system have been associated with fetal growth restriction in women. In human pregnancy, the proteolytic cleavage of insulin-like growth factor binding proteins (IGFBPs), particularly IGFBP-4, releases free IGF for respective action at the tissue level. The aim of the present study was to determine IGFBP-2, IGFBP-3, and IGFBP-4 concentrations by Western ligand blotting during pregnancy until day 100 in cows and to compare these concentrations with those of non-pregnant cows and cows undergoing embryonic/fetal mortality. Therefore, two study trials (I and II) and an in vitro study were conducted. In study I, 43 cows were not pregnant, 34 cows were pregnant, and 4 cows were undergoing fm. In study II, 500 cows were examined, and 7 cases of pregnancy loss between days 24–27 and 34–37 after artificial insemination (AI, late embryonic mortality; em) and 8 cases of pregnancy loss between days 34–37 and 54–57 after AI (late embryonic mortality and early fetal mortality; em/fm) were defined from the analyses of 30 pregnant and 20 non-pregnant cows randomly selected for insulin-like growth factor 1 and IGFBP analyses. In vitro serum from pregnant (n = 3) and non-pregnant (n = 3) cows spiked after incubation with recombinant human (rh) IGFBP-4 for 24 h, and IGFBP-4 levels were analyzed before and after incubation to detect proteolytic degradation. The IGFBP-2, -3, and -4 concentrations did not decline during early pregnancy in cows, while IGFBP-4 concentrations were comparable between pregnant and non-pregnant cows, irrespective of low proteolytic activity, which was also demonstrated in cows. Interestingly, cows with em or fm showed distinct IGFBP patterns. The IGFBP-2 and -3 concentrations were higher (P < 0.05) in cows with fm compared to pregnant. The IGFBP-4 levels were significantly higher in cows developing fm. Thus, distinct differences in the circulating IGFBP concentrations could be associated with late embryonic and early fetal losses in cattle.

Highlights

The somatotropic axis is a key regulatory pathway for dairy cows, and a growth hormone insensitivity plays a role in energy partitioning to facilitate milk production after calving [1]
We conducted in vitro analyses to determine whether the proteolytic degradation of insulin-like growth factor binding proteins (IGFBPs)-4 is detectable in cows
In Study trial II, a higher number of animals (n = 500) was examined; 8 cows were found with late embryonic mortality, and 7 cows were found with late embryonic/early fm

Summary

Introduction

The somatotropic axis is a key regulatory pathway for dairy cows, and a growth hormone insensitivity plays a role in energy partitioning to facilitate milk production after calving [1]. High IGFBP-4 concentrations have previously been linked to fetal growth restriction in human gestation [14, 15], and less proteolytic cleavage might be due to higher IGFBP-4 and lower IGF-1 levels. Substantial differences in metabolic adaption throughout lactation may be responsible for differences in peripheral IGFBP-2 or IGFBP-4 concentrations and, play a role in pregnancy maintenance or serve as biomarker. It was previously indicated in dairy cows that a higher peripheral IGFBP-3 concentration was associated with a lower fertility rate [16]

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