Khoshkerdar, Afsaneh
(2024)
Defining the impact of paternal diet on maternal cardiometabolic ill-health in late gestation.
PhD thesis, University of Nottingham.
Abstract
It is well-established that poor maternal nutrition prior to, or during, pregnancy can have a range of adverse consequences for the health of the mother and her offspring. For the mother, these consequences can become manifest in an increased risk of developing conditions such as preeclampsia and gestational diabetes. For her offspring, studies have shown an increased predisposition towards a series of non-communicable diseases including obesity, type-2 diabetes, and cardiovascular disease. Such connections between maternal health and offspring well-being have been defined over recent decades through the detailed examination of human epidemiological cohorts as well as a multitude of animal models.
While the association between poor maternal health and perturbed offspring development is widely acknowledged, the role that a father plays in directing the development and long-term health of his offspring has been overlooked. However, it is becoming increasingly evident that the father plays a more significant role than just contributing to his progeny’s genome. Similar to the established maternal programming studies, the use of historical epidemiological data sets, supported by mechanistic animal models, reveals a complex process through which poor paternal health influences post-fertilization development and offspring well-being. Such observations have underpinned a new field within the Developmental Origins of Health and Disease (DOHaD) hypothesis, known as the Paternal Origins of Health and Disease (POHaD).
In particular, studies have focused on the role of paternal nutrition, being either increased or decreased in specific macro- and micro-nutrients including protein, fat, sugar and folate. Through these studies, a complex system involving perturbed testicular function and spermatogenesis, epididymal maturation and exosomal modifications, sperm epigenetic status and DNA integrity as well as seminal plasma composition have all been identified as mediators of paternal programming.
Therefore, this thesis aimed to investigate the impact of a paternal suboptimal diet on male physiology, fetal development, and late gestation maternal cardio-metabolic health. Furthermore, as altered sperm epigenetic status has been identified as one central programming mechanism, the impact of methyl-donor supplementation was also investigated to determine if this could negate the detrimental effects of the suboptimal diets. Additionally, as poor maternal health in pregnancy is a significant risk factor for altered fetal development, I also assessed the impact of paternal diet on maternal cardio-metabolic status in late gestation.
To achieve these aims, male C57/BL6J mice were fed one of the five diets; a control diet (CD, 18% casein, 21% sugar, 10% fat), low protein diet (LPD, 9% casein, 24% sugar, 10% fat), Western diet (WD, 19% casein, 34% sugar, 21% fat), LPD supplemented with methyl donors (MDLPD, 15% D, L-methionine, 7.5% betaine, 5% choline chloride) or WD supplemented with methyl donors (MDWD) for a minimum of 7 weeks. Males were mated with chow-fed, virgin 8–12-week-old C57BL/6J females. At embryonic day 17.5, dams were culled for the collection of a range of maternal and fetal tissues. At the end of the study, stud males were then culled for the analysis of male organ size.
I observed that male weight was not altered in response to being fed any of the experimental diets. However, I did observe differential sizing of several organs, especially within the WD and MDWD males. Of note, was an increase in gonadal fat in these males, indicating that while total body weight was not altered, adiposity appeared to increase. Following mating, there were no detrimental impacts of any diet on male fertility, as determined by late gestation litter size. While fetal growth and organ sizing appeared largely unaffected by the paternal diets, analysis of the fetal cardiac transcriptome revealed altered expression of multiple genes. In LPD and MDL fetuses, I observed differential expression of genes within central lipid, amino acid, and carbohydrate metabolic processes as well as cardiovascular disease pathways. In contrast, WD hearts demonstrated upregulation of genes involved in angiogenesis, embryonic organ development, and lipid metabolism as well as an abnormal heart morphology phenotype.
Analysis of placental morphology and gene expression revealed no difference in overall morphology or sizing of the labyrinth (Lz) or junctional (Jz) zones. Using Masson’s Trichrome staining to visualize the amount of connective tissue within the placenta, revealed a significant reduction in the amount of overall staining within WD and MDWD placentas. Furthermore, I observed reduced expression of genes central within the renin-angiotensin system (RAS), apoptosis and one-carbon metabolism pathways within WD and MDWD placentas.
Finally, analysis of maternal cardiometabolic health in late gestation showed there to be minimal changes in serum and hepatic metabolites, gut microbiota or mediators of cardiovascular function in response to paternal diet.
These observations are of interest to human health as they demonstrate that in pregnancies uncomplicated by male infertility, or perturbed by maternal metabolic health, fetal cardiovascular programming still occurred. Furthermore, changes in fetal cardiac gene expression occurred in response to both a relatively moderate (LPD) and severe (WD) paternal dietary challenge. Further studies are required to define the underlying mechanisms through which poor paternal diet impacts fetal heart gene expression and the consequences of these changes for long-term offspring health.
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