Origins of lifetime health around the time of conception: causes and consequences

Abstract

Parental environmental factors, including diet, body composition, metabolism, and stress, affect the health and chronic disease risk of people throughout their lives, as captured in the Developmental Origins of Health and Disease concept. Research across the epidemiological, clinical, and basic science fields has identified the period around conception as being crucial for the processes mediating parental influences on the health of the next generation. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune, and neurological morbidities, often termed developmental programming. We review periconceptional induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and the use of assisted reproductive treatment. Studies in both humans and animal models have demonstrated the underlying biological mechanisms, including epigenetic, cellular, physiological, and metabolic processes. We also present a meta-analysis of mouse paternal and maternal protein undernutrition that suggests distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.

Figure 1. Biological events underpinning periconceptional conditioning

The periconceptional period is one of extensive cellular change comprising the completion of meiotic maturation of oocytes, differentiation of spermatozoa, fertilisation and resumption of mitotic cell cycles in the zygote, marking the transition from parental to embryonic genomes and the onset of morphogenesis . Periconceptional biology is indeed ‘busy’ – the morphological and cellular changes occurring during the switch from parental to embryonic generations leading to blastocyst formation are driven by pronounced sub-cellular and molecular processes. These include global restructuring of the epigenome (mainly DNA methylation and histone modifications that control gene expression), such that expression from the new embryonic genome is distinct from the parental genomes. Epigenetic reorganisation allows the embryo to first exhibit totipotency, a naïve cellular state conferring the ability to construct both true embryonic (future fetal) cell lineages and the extra-embryonic (placental) lineages that become evident in the blastocyst. Subsequently, epigenetic modifications underpin embryo pluripotency, the capacity to generate all three germ layers (ectoderm, mesoderm, endoderm) once gastrulation has taken place. Morphogenesis of the blastocyst is followed by embryo hatching from the zona pellucida coat and implantation mediated through adhesion of the outer trophectoderm layer of the blastocyst to the uterine endometrium and subsequent invasion and decidualisation. Activation of the new embryonic genome before implantation not only permits de novo gene expression distinct from parental genomes but also involves establishment of the embryo’s metabolism that matures over time.

Figure 2. Summary of periconceptional developmental conditioning from the four areas reviewed with main mechanisms highlighted in the progression of disease risk. ICSI = intracytoplasmic sperm injection, IVF = in vitro fertilization.

Figure 3. Defining the relative influence of maternal and paternal factors during periconceptional conditioning in mice following parental low protein diet (LPD; 9 % casein).

The effect of parental LPD on (A) offspring weight at birth, (B) adult offspring systolic blood pressure (SBP), and (C) adult offspring heart:body weight ratio are shown when compared with offspring from normal protein diet (NPD; 18% casein) fed parents. Analysis of 4 studies involving female MF1 mice being fed LPD exclusively during the terminal stages of oocyte maturation (3.5 days prior to mating; Egg-LPD), exclusively during preimplantation embryo development (Emb-LPD) or throughout gestation (LPD). Forest plots also include offspring data in response to a paternal low protein (Pat-LPD) fed to C57BL6 males prior to mating. For Egg-NPD n = 189–80 from 19 litters; Egg-LPD n = 201-67 from 19 litters; NPD n = 131-76 from 19 litters; LPD n = 116-85 from 19 litters; Emb-LPD n = 134-78 from 19 litters; Pat-NPD n = 85-76 from 16 litters; Pat-LPD n = 73-62 from 16 litters. A. Plots present differences between means (± 95% CI) of birth weight (grams) to study specific NPD group. Data combining all LPD and all NPD treatment groups is used to determine the Pooled Estimate. Heterogeneity (χ²) between studies = 1.96 (3 df), I² = 33%. B. Plots present differences between means (± 95% CI) of adult SBP (mmHg) to study specific NPD group. Data combining all LPD and all NPD treatment groups is used to determine the Pooled Estimate. Heterogeneity (χ²) between studies = 1.05 (4 df), I² = 39%. C. Plots present differences between means (± 95% CI) of heart:body weight ratio to study specific NPD group. Data combining all LPD and all NPD treatment groups is used to determine the Pooled Estimate. heterogeneity (χ²) between studies = 1.86 (3 df), I² = 61%.