Issue 50 – Winter 2020

It is commonly thought that the origin of non communicable disease in later life lies either in our unhealthy adult lifestyle or in inheriting a defective parental gene. However, disease risk can be traced back to gestation and, for example, the quality of nutrition provided by mothers. Thus, lower birthweight across the normal range increases cardiometabolic disease susceptibility in adulthood. This concept is known as the developmental origins of health and disease (DOHaD).1 We can now pinpoint the time around conception as possibly the most critical window for environment to influence development and health over a lifetime. This was seen, for example, in the descendants of the Dutch Hunger Winter of the Second World War.2,3 Periconception The period around conception, or periconception (PC), broadly covers the final maturation of male and female gametes, fertilisation and early development of the embryo up to implantation into the endometrium: a few weeks in our lives. Whilst PC is recognised for its reproductive importance and establishment of a viable embryo, it is also when external stimuli can modulate this progression, with enduring consequences. Diverse conditions across mammalian species, including humans, such as poor or over-rich maternal diet or alcohol consumption, similar lifestyle factors in fathers, and the altered in vitro environment experienced by assisted reproduction treatments (ARTs), can all affect PC in a DOHaD context. Adverse environments can change the developmental programme, altering growth, metabolism, gene expression and physiology with remarkable long term outcomes, leading to increased cardiovascular and metabolic syndrome risks and neurological ill-health in adulthood.2−4 Maternal obesity effects Mechanistic understanding of this phenomenon has come largely from controlled animal models, but is supported by evidence from clinical studies. Adverse programming may derive by means of early perturbations to reproductive tissues. Thus, fatty acids and hyperglycaemic metabolites accumulate within ovarian follicular fluid as a result of maternal obesity and high fat diet. These rich nutrients seep into the oocyte and persist in the early embryo, causing metabolic oxidative stress and reducing mitochondrial function and energy production.5,6 Whilst maternal obesity is known to reduce fertility, these cellular consequences also change the metabolic homeostasis of the fetus and offspring, altering the growth trajectory and conferring increased adiposity risk in offspring.7

Maternal undernutrition The PC environment can also induce an adaptive capacity in the embryo to optimise development dependent upon maternal nutrition. Such a strategy permits morphogenesis over the duration of pregnancy to be co-ordinated by local conditions. The converse of obesity, that of maternal protein restriction (a status more commonplace in evolution), acts accordingly. Thus, maternal protein deprivation reduces amino acid availability systemically but also within the uterine lumen, where early developing embryos are bathed before implantation. Here, the embryo has sensing mechanisms to detect selected amino acid levels. It responds to deficiency by activating signalling pathways, driving compensatory processes to form a more efficient placenta and yolk sac, thereby protecting nutrient supply from the mother.9 Health problems materialise if maternal nutrition changes in later pregnancy, causing early adaptations to become unnecessary, resulting in overgrowth, adiposity and increased adult disease risk.2,3 Importance of epigenetics PC programming of an individual’s phenotype requires a ‘biological memory’ of the early environment to persist across the lifespan. This is achieved through the global epigenetic restructuring that occurs soon after fertilisation, and concurrent with the activation of the new embryonic genome. DNA demethylation of paternally and maternally inherited alleles occurs during cleavage of the zygote. It is followed by remethylation of the genome, to co-ordinate the developmental programme, after blastocyst formation and during differentiation of embryonic and extra-embryonic lineages.10 Disturbance or compensatory modification of this delicate process has been demonstrated in response to several PC DOHaD models, leading to persistent (lifetime) change in the pattern and extent of gene expression. One illustration is the relative level of methylation of the rDNA genes, which inversely regulates transcription of rRNA for ribosome biogenesis, to fine-tune protein translation and growth. Here, PC maternal protein restriction activates this epigenetic mechanism to optimise growth across somatic tissues through to adulthood.11 Clinical implications There are significant clinical implications to consider in this field. An ART randomised controlled trial has shown human birthweight varies dependent upon the selection of embryo culture medium some 9 months earlier.12 Children conceived by ART also demonstrate increased cardiometabolic health risks and altered epigenetic status during their life, compared with the naturally conceived population.2,3 Similar datasets using fertile animal models indicate these outcomes are not caused by patient infertility. Clearly, pregnancy needs to be approached with a healthy lifestyle not just for reproductive success but for the well-being of the next generation − no pressure there then. Tom P Fleming School of Biological Sciences, University of Southampton, Southampton, UK