Review
Peri-conception parental obesity, reproductive health, and transgenerational impacts

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Highlights

  • Maternal obesity changes oocyte composition altering lipid content and mitochondrial function.

  • Maternal obesity-induced changes impact on embryo development, programming disease risk in offspring.

  • Paternal obesity at conception impairs the metabolic and reproductive health of the offspring through two generations.

  • Paternal obesity alters epigenetic marks in sperm implicating these changes in the transmission of paternal health cues to the next generation.

Maternal over-nutrition during pregnancy is a risk factor for pregnancy complications and is increasingly associated with adverse childhood outcomes such as increased propensity for obesity and metabolic disease. However, there is emerging evidence that parental lifestyle factors prior to and at conception have a powerful impact on the health of the offspring for more than one generation. Maternal and paternal obesity prior to conception alters the molecular composition of both oocytes and sperm, which can partly escape epigenetic reprogramming at fertilization, altering the developmental trajectory of the resultant embryo, ultimately increasing the incidence of obesity and metabolic disorders in offspring. Understanding the molecular underpinning of these changes may help create interventions to reduce the risk of disease in future generations.

Section snippets

Developmental programming of disease risk

In a series of early studies by David Barker and colleagues, it was shown that in utero exposures left a legacy on an individual's physiology, ‘programming’ their susceptibility to disease [1]. Numerous studies have since substantiated this hypothesis, such that it is now well accepted that the maternal environment during pregnancy is an important factor in influencing our growth trajectories before birth, and informing our risk to disease in later life. However, there is emerging evidence that

Maternal obesity impacts fertility, embryo, and offspring

It is well understood that maternal obesity can have a profound impact on a women's fertility as evident by alterations to hormone levels, anovulation, increased time to conception, decreased conception rates (both natural and after assisted conception), and increased rates of early miscarriage [3]. These influences suggest changes to the oocyte and early embryo that are distinct from the in utero effects of obesity and gestation weight gain, which also perturb fetal growth [3]. Maternal

Peri-conception female nutrition impacts on offspring

Interestingly, it was recently reported that the genome of Gambian infants conceived in the rainy season had different DNA methylation patterns than infants conceived in the harvest season, correlating with the seasonal variations in methyl-donor nutrient intake of mothers around the time of conception [17]. Identical epigenetic changes (increased or decreased DNA methylation at metastable epialleles) were observed in circulating lymphocytes as well as hair follicle cells, indicating they were

Influence of maternal metabolic health on oocyte composition

Maternal diet and obesity can also significantly impact oocyte quality. Obese female mice have increased rates of ovarian apoptosis, less mature oocytes after ovulation, slower preimplantation embryo development, and perturbed embryo differentiation to inner cell mass and trophectoderm lineage, defects that were improved upon treatment with insulin sensitizing drugs that promote weight loss and improve glucose homeostasis [23]. Mouse models of obesity have also found that females fed a HFD had

Is there a contribution of paternal programming?

The evidence regarding paternal programming in humans is still limited relative to maternal factors, compounded by the fact that many current population/cohort studies use male exposures to lifestyle and environment as a control for the postnatal environment of the mother and child in studies on maternal exposures [7]. Such a methodology necessitates the viewpoint that the paternal contribution to conception (i.e., the sperm, seminal plasma) is simply in a passive role with no impact on the

Animal studies of paternal programming

To counteract the difficulties in confounders associated with human studies, several rodent models have been developed to assess the impacts of transmission of phenotypes down the paternal line. The first of these involved the exposures of pregnant mothers to environmental toxins (i.e., in utero exposures of the male), where a series of papers demonstrated alterations to the F1–F3 phenotype that was transmitted through the paternal line, including transgenerational phenotypic changes that

Impacts of obesity on sperm function

There is now general acceptance that increasing male BMI results in perturbations to the hormonal axis of the male, reducing testosterone levels, which in turn impacts on spermatogenesis and sperm function 51, 52, 53. A recent systematic review of male obesity demonstrated a clear effect of male BMI on sperm concentration and also on sperm morphology [54]. While the impact on motility and in particular progressive motility is less clear, there is also consensus that male BMI is associated with

Mechanisms for parental transmission of offspring subfertility

The mechanism for parental transmission of peri-conception health is most likely from changes to the sperm and oocyte (Figure 1). During early development, the early embryo undergoes substantial epigenetic remodeling at both the DNA and chromatin level to give rise to a totipotent embryo combining both maternal- and paternal-derived genetic and epigenetic information [62]. Once re-established in a lineage- and tissue-specific fashion, epigenetic marks are carried forward into every subsequent

Concluding remarks and future perspectives

There is an increasing awareness that our environmental exposures impact our entire body's physiology, including that of our gametes. That the molecular composition and epigenetic signatures of these cells may be altered by dietary exposures represents a new set of risk factors for the next generation. Further, independently maternal and paternal BMI increase the risk for offspring to also become obese, with increased risk of metabolic disease, raising the further question as to whether two

Acknowledgments

M.L. is supported by a National Health and Medical Research Council (NHMRC) Research Fellowship. R.R. is supported by an NHMRC RD Wright Biomedical Research Fellowship.

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