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.

Amino Acid Transport and Metabolism Regulate Early Embryo Development: Species Differences, Clinical Significance, and Evolutionary Implications

“…However, for mammalian ES progenitor cells in the ICM, we suggest that Lys deprivation, owing to maternal LPDs, adversely alters the ICM production of tissues and organs in newborns and adults [24]. Unwanted effects of maternal LPD consumption during pre-and peri-implantation embryo development include metabolic syndrome and related disorders in adulthood [1,9,19,46,47].…”

“…More broadly regarding mTOR1 signaling and the development of trophoblast motility, a maternal low protein diet (LPD) during preimplantation development to the blastocyst stage led to a 25% reduction in the Leu concentration in mouse uterine fluid [45]. In a model, the latter authors proposed that the decreased uterine fluid Leu concentration results in less mTOR1 signaling, greater compensatory trophoblast pinocytosis and lysosome biogenesis, and increased histotrophic nutrition beginning at the blastocyst stage [46,47]. Consequently, offspring grow faster, have greater adiposity, and develop cardiovascular dysfunction, hypertension, neural abnormalities, and altered bone growth.…”

“…Consequently, offspring grow faster, have greater adiposity, and develop cardiovascular dysfunction, hypertension, neural abnormalities, and altered bone growth. This model may apply to all mammalian species, including humans, with invasive trophoblast implantation [46,47].…”

“…Blastocyst implantation in the uterus is crucial to mammalian species' survival, so it is not surprising that multiple mechanisms seem to fully support this process. Nevertheless, disturbances in the normal system B 0,+ functioning, such as maternal consumption of a LPD, apparently lead to greater adiposity, cardiovascular dysfunction, hypertension, neural abnormalities, and altered bone growth in adults [46,47]. In this regard, a culture of mouse blastocysts for only a few hours without amino acids decreases mTOR1 signaling, which is only partially restored by amino acid addition [104].…”

Epigenetic Modifications at the Center of the Barker Hypothesis and Their Transgenerational Implications

“…In species where blastocysts invade the uterine epithelium, B 0,+ promotes implantation and further development owing to Leu-stimulated mTOR1 signaling [ 35 , 36 , 37 , 38 , 39 ]. Since a maternal LPD during preimplantation development results in a Leu concentration decrease of about 25% in uterine secretions [ 40 ], Flemming and associates proposed that mTOR1 signaling would also be decreased [ 41 , 42 ]. In this model, increased trophoblast pinocytosis and lysosome biogenesis compensate to provide blastocysts and later stages greater histotrophic nutrition.…”