Prospective association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity.

BACKGROUND: Mitochondria are multifunctional energy-producing and signaling organelles that support life and contribute to stress adaptation. There is a growing understanding of the dynamic relationship between stress exposure and mitochondrial biology; however, the influence of stress on key domains of mitochondrial biology during early-life, particularly the earliest phases of intra-uterine/prenatal period remains largely unknown. Thus, the goal of this study was to examine the impact of fetal exposure to stress (modeled as the biological construct allostatic load) upon mitochondrial biology in early childhood. METHODS: In n = 30 children (range: 3.5-6 years, 53% male), we quantified mitochondrial content via citrate synthase (CS) activity and mtDNA copy number (mtDNAcn), and measured mitochondrial bioenergetic capacity via respiratory chain enzyme activities (complexes I (CI), II (CII), and IV (CIV)) in platelet-depleted peripheral blood mononuclear cells (PBMCs). In a cohort of healthy pregnant women, maternal allostatic load was operationalized as a latent variable (sum of z-scores) representing an aggregation of early-, mid- and late-gestation measures of neuroendocrine (cortisol), immune (interleukin-6, C-reactive protein), metabolic (homeostasis model assessment of insulin resistance, free fatty acids), and cardiovascular (aggregate systolic and diastolic blood pressure) systems, as well as an anthropometric indicator (pre-pregnancy body mass index [BMI]). RESULTS: An interquartile increase in maternal allostatic load during pregnancy was associated with higher mitochondrial content (24% and 15% higher CS and mtDNAcn), and a higher mitochondrial bioenergetic capacity (16%, 23%, and 25% higher CI, CII and CIV enzymatic activities) in child leukocytes. The positive association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity remained significant after accounting for the effects of key pre- and post-natal maternal and child covariates (p's < 0.05, except CI p = 0.073). CONCLUSION: We report evidence that prenatal biological stress exposure, modeled as allostatic load, was associated with elevated child mitochondrial content and bioenergetic capacity in early childhood. This higher mitochondrial content and bioenergetic capacity (per leukocyte) may reflect increased energetic demands at the immune or organism level, and thus contribute to wear-and-tear and pathophysiology, and/or programmed pro-inflammatory phenotypes. These findings provide potential mechanistic insight into the cellular processes underlying developmental programming, and support the potential role that changes in mitochondrial content and bioenergetic functional capacity may play in altering life-long susceptibility for health and disease.

Telomere length in individuals with and without major depression and adverse childhood experiences.

Major depressive disorder (MDD) and adverse childhood experiences (ACE) are associated with poor physical and mental health in adulthood. One underlying mechanism might be accelerated cellular aging. For example, both conditions, MDD and ACE, have been related to a biological marker of cellular aging, accelerated shortening of telomere length (TL). Since MDD and ACE are confounded in many studies, we aimed with the current study to further disentangle the effects of MDD and ACE on TL using a full-factorial design including four carefully diagnosed groups of healthy participants and MDD patients with and without ACE (total N = 90, all without use of antidepressants). As dependent variable, TL was assessed in leukocytes. We found no group differences based on MDD and ACE exposure in TL. While TL was negatively associated with age and male sex, TL was not associated with any measure of severity of MDD, ACE or current stress. One possible explanation for our null result may be the comparatively good physical health status of our sample. Future research is needed to elucidate the relation of TL, MDD and ACE, taking potential effect modification by medication intake and physical health status into account.

Newborn insula gray matter volume is prospectively associated with early life adiposity gain.

BACKGROUND: The importance of energy homeostasis brain circuitry in the context of obesity is well established, however, the developmental ontogeny of this circuitry in humans is currently unknown. Here, we investigate the prospective association between newborn gray matter (GM) volume in the insula, a key brain region underlying energy homeostasis, and change in percent body fat accrual over the first six months of postnatal life, an outcome that represents among the most reliable infant predictors of childhood obesity risk. METHODS: A total of 52 infants (29 male, 23 female, gestational age at birth=39(1.5) weeks) were assessed using structural MRI shortly after birth (postnatal age at MRI scan=25.9(12.2) days), and serial Dual X-Ray Absorptiometry shortly after birth (postnatal age at DXA scan 1=24.6(11.4) days) and at six months of age (postnatal age at DXA scan 2=26.7(3.3) weeks). RESULTS: Insula GM volume was inversely associated with change in percent body fat from birth to six-months postnatal age and accounted for 19% of its variance (ß=-3.6%/S.D., P=0.001). This association was driven by the central-posterior portion of the insula, a region of particular importance for gustation and interoception. The direction of this effect is in concordance with observations in adults, and the results remained statistically significant after adjusting for relevant covariates and potential confounding variables. CONCLUSIONS: Altogether, these findings suggest an underlying neural basis of childhood obesity that precedes the influence of the postnatal environment. The identification of plausible brain-related biomarkers of childhood obesity risk that predate the influence of the postnatal obesogenic environment may contribute to an improved understanding of propensity for obesity, early identification of at-risk individuals, and intervention targets for primary prevention.

Influence of maternal thyroid hormones during gestation on fetal brain development.

Thyroid hormones (THs) play an obligatory role in many fundamental processes underlying brain development and maturation. The developing embryo/fetus is dependent on maternal supply of TH. The fetal thyroid gland does not commence TH synthesis until mid gestation, and the adverse consequences of severe maternal TH deficiency on offspring neurodevelopment are well established. Recent evidence suggests that even more moderate forms of maternal thyroid dysfunction, particularly during early gestation, may have a long-lasting influence on child cognitive development and risk of neurodevelopmental disorders. Moreover, these observed alterations appear to be largely irreversible after birth. It is, therefore, important to gain a better understanding of the role of maternal thyroid dysfunction on offspring neurodevelopment in terms of the nature, magnitude, time-specificity, and context-specificity of its effects. With respect to the issue of context specificity, it is possible that maternal stress and stress-related biological processes during pregnancy may modulate maternal thyroid function. The possibility of an interaction between the thyroid and stress systems in the context of fetal brain development has, however, not been addressed to date. We begin this review with a brief overview of TH biology during pregnancy and a summary of the literature on its effect on the developing brain. Next, we consider and discuss whether and how processes related to maternal stress and stress biology may interact with and modify the effects of maternal thyroid function on offspring brain development. We synthesize several research areas and identify important knowledge gaps that may warrant further study. The scientific and public health relevance of this review relates to achieving a better understanding of the timing, mechanisms and contexts of thyroid programing of brain development, with implications for early identification of risk, primary prevention and intervention.

Association of maternal prepregnancy BMI with metabolomic profile across gestation.

BACKGROUND/OBJECTIVES: Elevated prepregnancy body mass index (pBMI) and excess gestational weight gain (GWG) constitute important prenatal exposures that may program adiposity and disease risk in offspring. The objective of this study is to investigate the influence of pBMI and GWG on the maternal metabolomic profile across pregnancy, and to identify associations with birth weight. SUBJECTS/METHODS: This is a longitudinal prospective study of 167 nondiabetic women carrying a singleton pregnancy. Women were recruited between March 2011 and December 2013 from antenatal clinics affiliated to the University of California, Irvine, Medical Center. Seven women were excluded from analyses because of a diagnosis of diabetes during pregnancy. A total of 254 plasma metabolites known to be related to obesity in nonpregnant populations were analyzed in each trimester using targeted metabolomics. The effects of pBMI and GWG on metabolites were tested through linear regression and principle component analysis, adjusting for maternal sociodemographic factors, diet, and insulin resistance. A Bonferroni correction was applied for multiple comparison testing. RESULTS: pBMI was significantly associated with 40 metabolites. Nonesterified fatty acids (NEFA) showed a strong positive association with pBMI, with specificity for mono-unsaturated and omega-6 NEFA. Among phospholipids, sphingomyelins with two double bonds and phosphatidylcholines containing 20:3 fatty acid chain, indicative of omega-6 NEFA, were positively associated with pBMI. Few associations between GWG, quality and quantity of the diet, insulin resistance and the maternal metabolome throughout gestation were detected. NEFA levels in the first and, to a lesser degree, in the second trimester were positively associated with birth weight percentiles. CONCLUSIONS: Preconception obesity appears to have a stronger influence on the maternal metabolic milieu than gestational factors such as weight gain, dietary intake and insulin resistance, highlighting the critical importance of preconception health. NEFA in general, as well as monounsaturated and omega-6 fatty acid species in particular, represent key metabolites for a potential mechanism of intergenerational transfer of obesity risk.

Association of ultrasound-based measures of fetal body composition with newborn adiposity.

BACKGROUND: Newborns exhibit substantial variation in gestational age-adjusted and sex-adjusted fat mass proportion. The antecedent characteristics of fetal body composition that are associated with newborn fat mass proportion are poorly understood. OBJECTIVE: The aim of this study was to determine whether a composite measure of fetal fat mass is prospectively associated with newborn adiposity. METHODS: In a longitudinal study of 109 low-risk pregnancies, fetal ultrasonography was performed at approximately 12, 20 and 30 weeks gestation. Estimated fetal adiposity (EFA) was derived by integrating cross-sectional arm and thigh per cent fat area and anterior abdominal wall thickness. Newborn per cent body fat was quantified by Dual Energy X-Ray Absorptiometry. The association between EFA and newborn per cent body fat was determined by multiple linear regression. RESULTS: After controlling for confounding factors, EFA at 30 weeks was significantly associated with newborn per cent body fat (standardized ß = 0.41, p < 0.001) and explained 24.0% of its variance, which was substantially higher than that explained by estimated fetal weight (8.1%). The observed effect was driven primarily by arm per cent fat area. CONCLUSIONS: A composite measure of fetal adiposity at 30 weeks gestation may constitute a better predictor of newborn per cent body fat than estimated fetal weight by conventional fetal biometry. Fetal arm fat deposition may represent an early indicator of newborn adiposity. After replication, these findings may provide a basis for an improved understanding of the ontogeny of fetal fat deposition, thereby contributing to a better understanding of its intrauterine determinants and the development of potential interventions.

Working memory performance is associated with common glucocorticoid receptor gene polymorphisms.

Cortisol has a modulatory influence on cognitive functions in humans. Both impairing and enhancing effects of cortisol administration have been shown for hippocampus-dependent declarative memory, and impairing effects have been shown for prefrontal-cortex-dependent working memory function. Given the high density of glucocorticoid (GC) receptors in the prefrontal cortex, we investigated whether common polymorphisms of the GC receptor (GR) gene (ER22/23EK, N363S, BclI, 9 beta A3669G) modulate the influence of cortisol administration on working memory. Working memory performance was investigated in 169 subjects on 10 mg hydrocortisone (cortisol) and placebo using an item recognition task. No impairing effect of hydrocortisone treatment became evident. However, a sex x genotype interaction on general working memory performance was revealed (p = 0.02). While female heterozygous carriers of the 9 beta G allele displayed faster reaction times than the other genotype groups, 9 beta G heterozygous men were relatively slower. Heritability estimates for memory are roughly 50%, indicating that common genetic polymorphisms have an important impact on cognitive performance. Our results suggest that variants of the GR gene might explain some of the variance attributable to genetic factors. Furthermore, it can be speculated that they modulate the individual vulnerability for memory impairments related to stress-related psychiatric disorders.

Glucocorticoid receptor gene polymorphisms and glucocorticoid sensitivity of subdermal blood vessels and leukocytes.

A considerable variability in the sensitivity to glucocorticoids (GCs) exists between individuals and these differences have been implicated in the etiology of psychiatric diseases such as depression. Glucocorticoid receptor (GR) gene polymorphisms might account in part for variability in GC responsiveness. We assessed the association between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and markers of glucocorticoid sensitivity in two target tissues (subdermal blood vessels, peripheral leukocytes) in 206 healthy individuals. The BclI GG genotype group showed the least degree of skin blanching, reflecting a lower GC sensitivity of subdermal blood vessels (p=.01). No association between GR genotype and GC sensitivity of peripheral leukocytes was observed. In the same subjects we previously observed an association between GR genotype and GC sensitivity of the pituitary. Polymorphism of the GR gene might constitute a vulnerability or protection factor for stress related disorders and altered GC sensitivity.

Cortisol and ACTH responses to psychosocial stress are modulated by corticosteroid binding globulin levels.

The hypothalamus-pituitary-adrenal (HPA) axis is vital for an organisms' response to physiological and psychological stress. Cortisol, secreted upon activation of the HPA axis, impacts on physiological systems throughout the organism. Responses to cortisol are influenced and modified by a number of factors, including corticosteroid binding globulin (CBG) levels. A major part of circulating cortisol is bound to CBG and only the unbound fraction is thought to be biologically active. The aim of the present study was to examine the modulating effect of CBG levels on hormonal responses following psychosocial stress in women using oral contraceptives (n=115) and in medication-free men (n=93). In women, CBG levels were negatively associated with ACTH and salivary cortisol and positively with total cortisol levels following the TSST. In men, positive associations were observed between CBG and ACTH and total cortisol levels following the TSST. CBG is an important regulatory element of HPA axis response patterns; therefore, CBG levels have to be taken into account as a potential modifier of ACTH and cortisol responses to psychosocial and pharmacological stimulation. Investigations of the consequences of long-lasting OC intake on the neuroendocrine stress regulation in women might be warranted.