Background: Intrauterine growth restriction (IUGR), commonly resulting from uteroplacental insufficiency (UPI), impairs fetal growth and leads to infants being born small for gestational age. Individuals affected by IUGR are at increased risk of developing chronic diseases later in life.
Methods: Using a rat model of UPI-induced IUGR, we examined the transgenerational effects of growth restriction on physiological and metabolic outcomes in offspring across multiple generations transmitted through the paternal lineage. Renal gene expression profiles were also assessed in F1, F2, and F3 offspring using RNA sequencing.
Results: Accelerated postnatal growth was observed in both male and female offspring in the F2 and F3 generations. Changes in postmortem organ weights was seen in F2 and F3 offspring. At 12 months of age, F3 males and females had impaired insulin secretion, characterised by a 40% reduction in first-phase insulin secretion in IUGR males and a 20% reduction in second-phase insulin secretion in IUGR females compared with sex-matched controls. In contrast to findings in the maternal lineage, no significant differences in blood pressure were detected in F2 or F3 IUGR offspring from the paternal line. Transcriptomic analysis revealed persistent molecular alterations in the kidneys of F1, F2, and F3 offspring, including changes in several imprinted genes.
Conclusions: UPI-induced IUGR results in transgenerational physiological and molecular adaptations extending through the paternal lineage. These changes included alterations in organ weights, impaired metabolic function, and renal molecular dysregulation, across several generations. While changes in organ weights were evident in paternal-line descendants, vascular and metabolic dysfunction are more pronounced in offspring from the maternal lineage, highlighting lineage-specific patterns of transgenerational inheritance.