Environmental Exposures around Conception: Developmental Pathways Leading to Lifetime Disease Risk

Abstract

Environment around conception can influence the developmental programme with lasting effects on gestational and postnatal phenotype and with consequences for adult health and disease risk. Peri-conception exposure comprises a crucial part of the 'Developmental Origins of Health and Disease' (DOHaD) concept. In this review, we consider the effects of maternal undernutrition experienced during the peri-conception period in select human models and in a mouse experimental model of protein restriction. Human datasets indicate that macronutrient deprivation around conception affect the epigenome, with enduring effects on cardiometabolic and neurological health. The mouse model, comprising maternal low protein diet exclusively during the peri-conception period, has revealed a stepwise progression in altered developmental programming following induction through maternal metabolite deficiency. This progression includes differential effects in extra-embryonic and embryonic cell lineages and tissues, leading to maladaptation in the growth trajectory and increased chronic disease comorbidities. The timeline embraces an array of mechanisms across nutrient sensing and signalling, cellular, metabolic, epigenetic and physiological processes with a coordinating role for mTORC1 signalling proposed. Early embryos appear active participants in environmental sensing to optimise the developmental programme for survival but with the trade-off of later disease. Similar adverse health outcomes may derive from other peri-conception environmental experiences, including maternal overnutrition, micronutrient availability, pollutant exposure and assisted reproductive treatments (ART) and support the need for preconception health before pregnancy.

Keywords: DOHaD; blastocyst; low protein diet; mTORC1; maternal undernutrition; peri-conception; primitive endoderm; ribosome biogenesis; trophectoderm; uterine fluid.

Figure 1

Diagrammatic representation of the maternal Emb-LPD mouse model. Maternal low protein diet is provided exclusively for the preimplantation period with normal nutrition, thereafter leading to co-morbidities affecting growth, cardiometabolic, neurological and skeletal health. Key references for these outcomes are identified, in sequence being 40, 42, 43, 1, 44, 2. See text for details.

Figure 2

Diagrammatic representation of the stepwise nature of altered developmental programme mediated through maternal Emb-LPD. (a) Overview, from BCAA (branched-chain amino acid) depletion in uterine fluid, reducing mTORC1 signalling in the blastocyst, leading to distinct changes in extra-embryonic and embryonic tissues and later-life disease. (b) Activation of increased histotrophic nutrition in trophectoderm (TE) mediated through low BCAA availability and TFEB translocation. A similar mechanism occurs in the primitive endoderm (PE) derivatives. Orange numbers represent steps in induction of histotrophic nutrition listed on the right where black arrows indicate increased or decreased levels/activity. (c) Activation of altered ribosome biogenesis in somatic tissues (derived from Epiblast) mediated through dietary sensing, RRN3 expression and rRNA transcription. Orange numbers represent steps in induction listed on the centre/right and, for 3, the effect of diet on ribosome biogenesis (bottom left) and life stage (bottom right). Key references for these outcomes are identified; in sequence being (a) 46; (b) 63 and 65; (c) 94. See text for details.