Infant HPA axis as a potential mechanism linking maternal mental health and infant telomere length☆
Introduction
Shorter telomere length (TL) is associated with early life stress and negative health trajectories across the lifespan (Drury et al., 2012, Shalev, 2012, Shalev et al., 2013). Therefore, it is important to identify early life factors that are associated with TL to better understand the emergence of divergent health trajectories. Indeed, the mechanistic origins of adult disease and psychopathology can often be traced back to early developmental disturbances that are both psychological and biological in nature (Shonkoff et al., 2009). Research has begun to elucidate how maternal mental health and offspring hypothalamic-pituitary-adrenal axis (HPA) stress response are independently associated with adolescent offspring TL (Gotlib et al., 2015). Importantly, questions remain as to when these divergent health trajectories begin, as well as the etiological pathways that mediate the effects of maternal mental health factors on the biological aging of infants in early life.
Telomeres are repeated nucleotide sequences (TTAGGG) at the end of eukaryotic chromosomes that protect chromosomes from deterioration and enable cellular integrity (Blackburn and Epel, 2012). During somatic cell division DNA polymerase is not able to fully replicate the 3′ end of linear DNA resulting in a progressive loss of telomeric repeats (Blackburn, 1991). TL is affected by age and genetics, indicating that telomere length is a “biological clock”, which is also influenced by environmental factors, such as cumulative exposure to lifetime stressors (Aviv, 2008, Olovnikov, 1996). Shorter TL is associated with stressful life events, as well as a range of negative health outcomes (i.e., cardiovascular disease, dementia, diabetes, cancer, obesity, and early mortality; see Blackburn and Epel, 2012), while longer TL length is associated with both positive social relationships (Uchino et al., 2012) and mindfulness (Blackburn and Epel, 2012, Hoge et al., 2013; Jacobs et al., 2011). Cortisol, the end product of neuroendocrine activation, has been proposed to be one mechanism that is associated with TL and cell senescence (Shalev, 2012) as research has demonstrated that human T lymphocytes exposed to cortisol show reduced telomerase, the enzyme responsible for telomere maintenance (Choi et al., 2008), and reduced TL (Vartak et al., 2014). In addition, greater cortisol response to a laboratory stressor in young children (Kroenke et al., 2011) and adults (Tomiyama et al., 2012) is associated with shorter TL. Furthermore, adolescents of depressed mothers show both greater cortisol reactivity and shorter TL (Gotlib et al., 2015). Telomeres thus represent an important biomarker for the study of health risk and resilience processes.
Early relationships have implications for health outcomes across the lifespan (Shonkoff et al., 2009). Maternal psychological characteristics can serve as risk or protective factors for infant outcomes. For example, in terms of risk factors, maternal stress during pregnancy is associated with shorter infant TL (Send et al., 2017) and infants of depressed mothers tend to have greater cortisol reactivity to stress (Azar et al., 2007, Brennan et al., 2008). Furthermore, it is important to study changes across time in maternal mental health during infancy as these patterns have differential associations with infant cortisol response dynamics over the first 18 months of life (Laurent et al., 2011). Similarly, it is important to study changes in infant cortisol responses over time as research has shown that from 2 to 15 months of age infants tend to dampen their HPA responses to stressors even though they may show signs of behavioral distress (Gunnar et al., 1996). On the protective side, individual differences in mindfulness, the psychological capacity to maintain nonjudgmental awareness of the present moment (Kabat-Zinn and Hanh, 1990), may help with regulating one’s own and one’s infant’s stress. For example, women with greater levels of dispositional mindfulness tend to have more flexible HPA axis responses (i.e., quicker post-stress cortisol recovery; see Laurent et al., 2015), and mindfulness in the parenting relationship predicts both quicker maternal cortisol recovery and lower infant cortisol levels during stress (Laurent et al., 2017). Therefore, maternal depressive symptoms and mindfulness may be hypothesized as risk and protective factors, respectively, that influence infant stress responses – with risk factors increasing cortisol reactivity and slowing recovery, and protective factors lowering cortisol reactivity and quickening recovery. Research has yet to fully elucidate how maternal mental health impacts not only the stress response of their infants, but also their infant’s biological aging as reflected in TL.
Research indicates that oxidative stress via dysregulated HPA axis activation may be one mechanism that connects the exposure to early life stress and later TL (Shalev, 2012). Indeed, as mentioned above, T lymphocyte exposure to cortisol is associated with reduced activity of telomerase, an enzyme responsible for maintaining TL (Choi et al., 2008), and reduced TL (Vartak et al., 2014). Research further demonstrates independent associations between early life stress and increased cortisol reactivity in infants of depressed mothers (Azar et al., 2007, Brennan et al., 2008) and shortened TL (Drury et al., 2012, Price et al., 2013). This trend seems to persist into adolescence as healthy adolescent offspring of mothers with recurrent episodes of depression are at increased risk for altered HPA axis response to stress (i.e., greater cortisol reactivity) and shorter TL (Gotlib et al., 2015). However, research has yet to investigate these connections in an infant sample and investigate whether changes in infant HPA axis activity mediate the relationship between changes in maternal mental health and later infant TL. In other words, the conceptual model of maternal depressive symptoms acting as a stressor to influence infant cortisol response, which subsequently impacts infant TL has yet to be tested.
The current study investigated whether changes in maternal mental health predict changes in infant cortisol reactivity and recovery between 6 months and 12 months of age. Moreover, we investigated whether these patterns of cortisol reactivity and recovery mediated the relationship between changes in maternal mental health (depressive symptoms and mindfulness) during this time and subsequent infant TL at 18 months of age. First, we predicted that increased maternal depressive symptoms and decreased dispositional mindfulness would be associated with increased cortisol reactivity and incomplete cortisol recovery (i.e., greater return of cortisol to baseline levels after stress exposure) in infants. Second, we hypothesized that increased infant cortisol reactivity would predict shorter TL, while more complete infant cortisol recovery would predict longer TL. Finally, we hypothesized that change in maternal depressive symptoms and/or mindfulness would indirectly relate to subsequent infant TL due to change in infant cortisol response. In particular, mothers that showed increased depressive symptoms and/or decreased mindfulness from 6 to 12 months would have infants with increased cortisol reactivity and impaired cortisol recovery, and shorter telomeres at 18 months. This study was pre-registered with Open Science Framework (osf.io/rc824).
Section snippets
Participants and recruitment
Mothers were recruited from the Women Infants Children program and other community agencies serving low-income families in a mid-sized city in the pacific northwest of the United States. To be eligible, mothers had to speak English, have a ≪ 12-week-old infant, and anticipate remaining in the area until this target child was 18 months old. Table 1 gives demographic information about the sample at the first assessment.
Of the 91 mother-infant dyads who began the study at time 1, 48 dyads (53%)
Preliminary analyses
Correlation analyses using the corrplot R package (Wei and Simko, 2016) revealed that no covariates were associated with TL (Fig. 2 for correlation matrix among study variables). Infant and mother TL were significantly related (r = 0.350, 95% CI [0.073, 0.577], p = 0.015) and mother TL was significantly shorter than infant TL as expected, t(47) = 13.17, 95% CI [0.56, 0.76], p ≪ 0.001 (see Supplementary Material Fig. S1).
Main analyses: direct paths
Increase in infant cortisol reactivity between 6–12 months of age significantly
Discussion
The current study was designed to investigate the connection between changes in maternal risk (depressive symptoms) and protective (mindfulness) factors and concurrent changes in infants’ cortisol reactivity and recovery, and to test whether these coupled changes in maternal and infant health were associated with subsequent infant TL. This study is the first to examine the mediating role of infant HPA dynamics in the relationship between alterations in maternal mental health and infant
Conflict of interest
All authors declare no conflicts of interest.
Acknowledgments
This research was supported by grants from The Mind and Life Institute (1440 Research Award 2015-1440-Nelson) awarded to the first author and The Society for Research in Child Development Victoria Levin Award and the University of Oregon College of Arts and Sciences issued to the last author. The funding sources had no role in the study design, data collection and analysis, or submission process. We thank Elissa Epel, Ph.D. for her consultation on our study design and Jue Lin, Ph.D. and
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Open Science Framework Citation: osf.io/rc824