Maternal socioeconomic disadvantage is associated with transcriptional indications of greater immune activation and slower tissue maturation in placental biopsies and newborn cord blood

Abstract

Children from economically disadvantaged families experience worse cognitive, psychiatric, and medical outcomes compared to more affluent youth. Preclinical models suggest some of the adverse influence of disadvantage could be transmitted during gestation via maternal immune activation, but this hypothesis has not been tested in humans. It also remains unclear whether prenatal interventions can mitigate such effects. To fill these gaps, we conducted two studies. Study 1 characterized the socioeconomic conditions of 79 women during pregnancy. At delivery, placenta biopsies and umbilical blood were collected for transcriptional profiling. Maternal disadvantage was associated with a transcriptional profile indicative of higher immune activation and slower fetal maturation, particularly in pathways related to brain, heart, and immune development. Cord blood cells of disadvantaged newborns also showed indications of immaturity, as reflected in down-regulation of pathways that coordinate myeloid cell development. These associations were independent of fetal sex, and characteristics of mothers (age, race, adiposity, diabetes, pre-eclampsia) and babies (delivery method, gestational age). Study 2 performed the same transcriptional analyses in specimens from 20 women participating in CenteringPregnancy, a group-based psychosocial intervention, and 20 women in traditional prenatal care. In both placenta biopsies and cord blood, women in CenteringPregnancy showed up-regulation of transcripts found in Study 1 to be most down-regulated in conjunction with disadvantage. Collectively, these results suggest socioeconomic disparities in placental biology are evident at birth, and provide clues about the mechanistic origins of health disparities. They also suggest the possibility that psychosocial interventions could have mitigating influences.

Population-based RNA profiling in Add Health finds social disparities in inflammatory and antiviral gene regulation to emerge by young adulthood

“…Given the restricted age range in this sample, these data likely under-represent the total range of transcriptomic variation across the adult life span. These analyses document the presence of significant demographic differences in human genome function at the time of young adulthood, but it is possible that such differences emerge even earlier in development (e.g., adolescence, childhood, infancy, or in utero) (56)(57)(58)(59). A critical topic for future population-based genomic research will be pushing back the etiological time line even further than achieved here to identify the specific developmental periods in which the demographic differences in gene expression first appear.…”

Gene expression in cord blood links genetic risk for neurodevelopmental disorders with maternal psychological distress and adverse childhood outcomes

“…Significant differences in ME expression were observed in maternal depressionrlatd modules (b) M2 and (c) M13 and maternal PTSD-related modules (e) M3 and (f) M14. refers to an altered gene module in the cerebral cortex of ASD cases (M16 from the study) and Miller et al, 2017 refers to UCB gene expression profiles associated with maternal socioeconomic disadvantage. Overrepresentation analysis of these gene sets within network modules was analyzed using a one-sided Fishers exact test to assess the statistical significance.…”

“…Third, neurodevelopmental disorder genetic risk loci were curated from human whole-exome and genome-wide association studies of autism spectrum disorder (ASD) (Sanders et al, 2015), developmental delay (Gene2Phenotype, OMIM, 2017), intellectual disability (Parikshak et al, 2013), schizophrenia (Fromer et al, 2014) and epilepsy (EuroEPINOMICS- RES Consortium, 2014). We also curated lists of gene coexpression modules found to be dysregulated in the cerebral cortex of autistic cases (Voineagu et al, 2011) and differentially expressed genes in umbilical cord blood from neonates born to mothers with socio-economic disadvantage (Miller et al, 2017). Overrepresentation analysis was determined using a one-sided Fisher's exact test with Benjamini-Hochberg multiple test correction.…”

Maternal immune activation, central nervous system development and behavioral phenotypes

“…More recently, PNS has been identified as a risk factor for the development of neuropsychiatric disorders in offspring (Holloway et al, ; Khashan et al, ; Kinney, Munir, Crowley, & Miller, ; Tearne et al, ). While multifactorial in origin, systemic inflammation and immune activation appear again to converge on a common pathway (Gilman et al, ; Howerton & Bale, ; Miller et al, ; Slopen et al, ). Animal models of PNS, have demonstrated a pro‐inflammatory cytokine IL‐6 response, with microglial activation resulting in neurodevelopment effects similar to immunostimulant MIA prototypes (Diz‐Chaves et al, ; Gumusoglu et al, ).…”

“…Animal models of PNS, have demonstrated a pro‐inflammatory cytokine IL‐6 response, with microglial activation resulting in neurodevelopment effects similar to immunostimulant MIA prototypes (Diz‐Chaves et al, ; Gumusoglu et al, ). In human studies, stressors during pregnancy are associated with altered concentrations of inflammatory biomarkers in maternal circulation, greater expression of pro‐inflammatory transcripts in the placenta, and over‐production of pro‐inflammatory cytokines by immune cells in response to immunostimulants (Borders et al, ; Coussons‐Read, Okun, & Nettles, ; Ernst et al, ; Gilman et al, ; Miller et al, ). The reported cytokine responses depend on the type and timing of the prenatal stressor, with elevated levels of IL‐6 and CRP most commonly reported (Bronson & Bale, ; Coussons‐Read et al, ; Veru, Dancause, Laplante, King, & Luheshi, ) and more recently decreased levels of IL‐8 (Gilman et al, ).…”