Maternal smoking during pregnancy and infant stress response: Test of a prenatal programming hypothesis

Abstract

Background Maternal smoking during pregnancy (MSDP) is associated with early and long-term neurobehavioral deficits; however mechanisms remain unknown. We tested the hypothesis that MSDP programs the hypothalamic pituitary adrenocortical (HPA) axis of the offspring leading to adverse outcomes. In an intensive, prospective study, we investigated associations between MSDP and infant cortisol stress response and explored whether alterations in cortisol response were mediated by epigenetic modulation of the placental glucocorticoid receptor gene (NR3C1). Methods Participants were 100 healthy mother-infant pairs (53% MSDP-exposed; 42% female) from a low income, racially/ethnically diverse sample (55% minorities). MSDP was assessed by timeline followback interview verified by saliva and meconium cotinine. Infant cortisol responses to a neurobehavioral exam were assessed 7 times over the first postnatal month. Methylation of placental NR3C1 promoter exon 1F was assessed using bisulfite pyrosequencing in a subsample (n=45). Results MSDP-exposed infants showed significantly and persistently attenuated basal and reactive cortisol levels over the first postnatal month vs. unexposed infants. Exploratory analyses revealed that MSDP was associated with altered methylation of the placental NR3C1 promoter; degree of methylation of the placental NR3C1 was associated with infant basal and reactive cortisol over the first postnatal month and mediated effects of MSDP on infant basal cortisol. Conclusions Results provide initial support for our hypothesis that MSDP programs offspring HPA (dys) regulation. Epigenetic regulation of placental GR may serve as a novel underlying mechanism. Results may have implications for delineating pathways to adverse outcomes from MSDP.

Maternal psychosocial stress during pregnancy alters the epigenetic signature of the glucocorticoid receptor gene promoter in their offspring: a meta-analysis

“…As can be seen in Figure 1, 15 articles were excluded due to the lack of new human data reported (reviews, animal studies, and human reports where there was no prenatal stress assessment); a total of 10 papers analyzed diverse prenatal stressors in relation to NR3C1 promoter methylation. In order to homogenize the final sample, 3 additional papers were excluded from the metaanalysis: one of them since smoking during pregnancy was not considered as a psychosocial stressor, 26 and the remaining 2 since, as discussed in the introduction, PTSD status during pregnancy has been described to upregulate cortisol inactivation and decrease cortisol circulating levels, and not the other way around. 12,13 The resulting pool consisted of 7 selected papers for the meta-analysis.…”

Stunting at 5 Years Among SGA Newborns

“…On the other hand, inadequate GWG during pregnancy may increase fetal susceptibility to height deficit due to maternal smoking. Specifically, smoking during pregnancy likely leads to damage in fetal hypothalamic-pituitary-adrenal axis, 15 which can be worsened by inadequate GWG because fetal brain development relies on glucose and other nutrients from the mother. In addition, maternal smoking during pregnancy and inadequate GWG may both lead to IGF gene hypermethylation and thus reduced IGF levels.…”

“…12 SGA newborns with maternal smoking, alcohol use, and infectious diseases during pregnancy may have toxicant-induced epigenetic changes 13 and growth hormone deficiency due to impaired hypothalamic-pituitary-adrenal axis functions. [14][15][16][17] SGA newborns with maternal smoking and alcohol use during pregnancy are more likely to have poor family dietary habits such as high fat and sugar but low calcium, vitamin D, and protein intake. 18,19 SGA newborns with maternal smoking and hypertension during pregnancy may undergo insufficient intrauterine supply of oxygen and nutrition related to the restricted umbilical cord blood flow caused by high placental resistance and thus are more likely to experience intrauterine hypoxia, 20,21 which is related to poor early childhood physical growth.…”

Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

“…Such a relatively low degree of methylation was expected in this healthy cohort of term births and is similar to what has been previously reported. 6,[46][47][48] Female infants had significantly higher overall methylation compared with males (2.17 vs. 1.73 percent methylated respectively), with higher levels of methylation evident for females at CpG sites 7, 10, 12, and 13. Table 4 shows the results from the linear regression models for the associations between prenatal metals exposure categorized as tertiles and NR3C1 methylation.…”

“…4 A number of recent reports have also linked variation in the DNA methylation of NR3C1 promoter region to fetal and newborn neurobehavioral phenotypes. [5][6][7] Neurotoxic metals can cross the placenta from mother to child during gestation, [8][9][10][11] and can also bioaccumulate in the placenta and cause functional damage, which may in turn impact fetal development due to the essential role of the placenta in development and fetal programming. 12,13 Moreover, research increasingly suggests that the placental epigenome is mediating the impact of environmental toxicant exposure in relation to child health.…”