Early post-conception maternal cortisol, children’s HPAA activity and DNA methylation profiles

Abstract

The hypothalamic–pituitary–adrenal axis (HPAA) plays a critical role in the functioning of all other biological systems. Thus, studying how the environment may influence its ontogeny is paramount to understanding developmental origins of health and disease. The early post-conceptional (EPC) period could be particularly important for the HPAA as the effects of exposures on organisms’ first cells can be transmitted through all cell lineages. We evaluate putative relationships between EPC maternal cortisol levels, a marker of physiologic stress, and their children’s pre-pubertal HPAA activity (n=22 dyads). Maternal first-morning urinary (FMU) cortisol, collected every-other-day during the first 8 weeks post-conception, was associated with children’s FMU cortisol collected daily around the start of the school year, a non-experimental challenge, as well as salivary cortisol responses to an experimental challenge (all Ps<0.05), with some sex-related differences. We investigated whether epigenetic mechanisms statistically mediated these links and, therefore, could provide cues as to possible biological pathways involved. EPC cortisol was associated with >5% change in children’s buccal epithelial cells’ DNA methylation for 867 sites, while children’s HPAA activity was associated with five CpG sites. Yet, no CpG sites were related to both, EPC cortisol and children’s HPAA activity. Thus, these epigenetic modifications did not statistically mediate the observed physiological links. Larger, prospective peri-conceptional cohort studies including frequent bio-specimen collection from mothers and children will be required to replicate our analyses and, if our results are confirmed, identify biological mechanisms mediating the statistical links observed between maternal EPC cortisol and children’s HPAA activity.

Social and Biological Transgenerational Underpinnings of Adolescent Pregnancy

“…For example, the HPA axis starts to develop during the first few weeks post-conception with the differentiation of primordial cell lines that will give rise to the anterior pituitary, hypothalamus and adrenal cortex [105]. Consistent with this proposition, we have found evidence that suggests the existence of a link between early peri-conceptional maternal cortisol during the first 8 weeks post-conception and children's HPA axis basal activity and stress responsivity at the onset of puberty [86]. Specifically, mothers' cortisol during said period was associated with their 10-and 11-year-old daughters' "basal" cortisol and HPA axis reactivity to natural (onset of the academic year) and experimental (the Trier Social Stress Test; [106][107][108]) challenges.…”

“…Thus, changes in HPA axis ontogeny can result in changes in energy allocation patterns during development and, consequently, in the endocrine and metabolic regulation of other biological systems, including the reproductive, or hypothalamic-pituitarygonadal (HPG) axis. HPA axis programming begins before conception, during gametogenesis [63,83,84], and continues throughout gestation and early childhood [85,86]. Once functional, the HPA axis, in its energy regulation role, can affect the pace of growth and functional maturation of all other biological systems, including the HPG axis [87][88][89].…”

“…Specifically, mothers' cortisol during said period was associated with their 10-and 11-year-old daughters' "basal" cortisol and HPA axis reactivity to natural (onset of the academic year) and experimental (the Trier Social Stress Test; [106][107][108]) challenges. In our search for potential mechanisms explaining these associations, we observed differential DNA methylation in 11 genes associated with maternal cortisol early post-conception, including genes in biological pathways involving corticotropin-releasing hormone (CRH) [86]. CRH is produced by the hypothalamus in response to stress.…”

A Canadian perspective on the developmental origins of health and disease: understanding the past as a way forward

“…However, despite the identification of hundreds of genes as well as interacting (epi)genetic and environmental factors that contribute to disease susceptibility and behaviour, we still lack an understanding of the neurochemistry – the proteins and pathways – that lead from genes to behaviour. Barha et al 15 examined a potential mechanistic link between maternal stress hormone levels early post-conception and levels of DNA methylation and stress-responsivity in their children. Given that maternal anxiety and depression are related to adverse childhood experiences and negatively affect children’s behaviour, 16 – 18 these exposures provide potential pathways between maternal adverse childhood experiences and child psychopathology.…”

Feasibility of Continuous Distal Body Temperature for Passive, Early Pregnancy Detection

“…It is possible that the present lack of tools for conception detection makes the study of very early natural pregnancies challenging. If features such as those described here persist in larger cohorts, then continuous DBT may enable more precise study of the physiological changes associated with conception, including continuous glucose patterning 106,107 , salivary and urinary hormone output 113,114 , early cardiovascular remodeling 115 . Additionally, continuous data may allow definition of tighter critical windows for the impacts from maternal and environmental influences 8 .…”