Fathers That Are Born Small Program Alterations in the Next-Generation Preimplantation Rat Embryos1,2

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Abstract

Background: Low birth weight is associated with increased risk of adult cardiovascular and metabolic disease development, with recent studies highlighting transmission to subsequent generations via both maternal and paternal lines. However, the timing of parent-specific programming of disease risk to the next generation remains to be characterized.

Objective: The aim of this study was to examine how paternal low birth weight affects the cellular and molecular physiology of the next-generation [second-generation (F2)] blastocysts, before uterine implantation.

Methods: Uteroplacental insufficiency was surgically induced in Wistar Kyoto pregnant rats in late gestation, giving rise to first-generation restricted (born small) and sham-operated control (normal birth weight) male offspring, respectively. First-generation restricted and control male rats were naturally mated with normal females.

Results: Resultant F2 blastocysts derived from restricted males displayed reduced expression of growth regulatory genes of the mammalian target of rapamycin pathway compared with F2 control blastocysts (9–74%; P < 0.05). No differences were found in F2 restricted blastocyst structural characteristics, cell number, or carbohydrate utilization at the time of blastocyst retrieval or after 24 h of in vitro culture. However, histidine, methionine, pyruvate, serine, and tryosine consumption and aspartate and leucine production were greater in F2 restricted outgrowth than in controls (P < 0.05).

Conclusions: The findings from this study clearly indicate that male rat offspring born small, arising from uteroplacental insufficiency, have physiologic alterations that manifest as modifications in gene expression levels and nutrient metabolism of F2 blastocysts, even in the absence of overt cellular growth differences. These data demonstrate that growth restriction and associated disease risk have the capacity to be transmitted to the next generation of offspring via the male germ line and is manifest as early as the blastocyst stage of development.

Key Words

preimplantation rat blastocyst
uteroplacental insufficiency
transgenerational transmission
growth restriction
paternal line

Abbreviations

F0
generation naught, normal female or male animals
F1
first-generation
F2
second-generation
G2
second-stage blastocyst culture growth
GMOPS
3-morpholinopropane-1-sulfonic acid-buffered first-stage blastocyst culture growth
HSA
human serum albumin
ICM
inner cell mass
mTOR
mammalian target of rapamycin
Pi3k
phosphoinositide 3 kinase
restricted
offspring born of low birth weight after bilateral uterine vessel ligation surgery
1H-NMR
hydrogen-1 nuclear magnetic resonance

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1

Supported by NHMRC project grant (to DKG and MEW), NHMRC Early Career Research fellowship (to NJH), Fay Marles Scholarship from The University of Melbourne (to JSM), and an MMI-CSIRO scholarship (to JSM).

2

Author disclosures: JS Master, GA Thouas, AJ Harvey, JR Sheedy, NJ Hannan, DK Gardner, and ME Wlodek, no conflicts of interest. The funding entity did not have a role in the design, implementation, analysis, or interpretation of the data. The findings and conclusions in this report are those of the authors.