Kelly J Brunst1, Marco Sanchez-Guerra2, Yueh-Hsiu Mathilda Chiu3, Ander Wilson4, Brent A Coull5, Itai Kloog6, Joel Schwartz7, Kasey J Brennan8, Michelle Bosquet Enlow9, Robert O Wright10, Andrea A Baccarelli11, Rosalind J Wright12. 1. Department of Environmental Health, University of Cincinnati College of Medicine, 160 Panzeca Way, Cincinnati, OH 45267, United States. Electronic address: kelly.brunst@uc.edu. 2. Department of Developmental Neurobiology, National Institute of Perinatology, Montes Urales 800, Lomas Virreyes, Mexico City 11000, Mexico. Electronic address: msanchezguerra@alumni.harvard.edu. 3. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, United States. Electronic address: mathilda.chiu@mssm.edu. 4. Department of Statistics, Colorado State University, Fort Collins, CO, United States. Electronic address: ander.wilson@colostate.edu. 5. Department of Biostatistics, Harvard T.H. Chan School of Public Health, 655 Huntington Ave., Boston, MA 02115, United States. Electronic address: bcoull@hsph.harvard.edu. 6. Department of Geography and Environmental Development, Ben-Gurion University of the Negev, P.O.B 653, Beer Sheva, Israel. Electronic address: ikloog@bgu.ac.il. 7. Department of Environmental Health, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States. Electronic address: jschwrtz@hsph.harvard.edu. 8. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, 722 W 168th St., New York, NY 10032, United States. Electronic address: Kasey.brennan@columbia.edu. 9. Department of Psychiatry, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02215, United States; Department of Psychiatry, Harvard Medical School, 401 Park Dr., Boston, MA 02215, United States. Electronic address: Michelle.Bosquet@childrens.harvard.edu. 10. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, 17 East 102nd St., New York, NY 10029, United States; Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, 17 East 102nd St., New York, NY 10029, United States. Electronic address: robert.wright@mssm.edu. 11. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, 722 W 168th St., New York, NY 10032, United States. Electronic address: andrea.baccarelli@columbia.edu. 12. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, United States; Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, 17 East 102nd St., New York, NY 10029, United States. Electronic address: Rosalind.wright@mssm.edu.
Abstract
BACKGROUND: Prenatal ambient fine particulate matter (PM2.5) and maternal chronic psychosocial stress have independently been linked to changes in mithochondrial DNA copy number (mtDNAcn), a marker of mitochondrial response and dysfunction. Further, overlapping research shows sex-specific effects of PM2.5 and stress on developmental outcomes. Interactions among PM2.5, maternal stress, and child sex have not been examined in this context. METHODS: We examined associations among exposure to prenatal PM2.5, maternal lifetime traumatic stressors, and mtDNAcn at birth in a sociodemographically diverse pregnancy cohort (N=167). Mothers' daily exposure to PM2.5 over gestation was estimated using a satellite-based spatio-temporally resolved prediction model. Lifetime exposure to traumatic stressors was ascertained using the Life Stressor Checklist-Revised; exposure was categorized as high vs. low based on a median split. Quantitative real-time polymerase chain reaction (qPCR) was used to determine mtDNAcn in placenta and cord blood leukocytes. Bayesian Distributed Lag Interaction regression models (BDLIMs) were used to statistically model and visualize the PM2.5 timing-dependent pattern of associations with mtDNAcn and explore effect modification by maternal lifetime trauma and child sex. RESULTS: Increased PM2.5 exposure across pregnancy was associated with decreased mtDNAcn in cord blood (cumulative effect estimate=-0.78; 95%CI -1.41, -0.16). Higher maternal lifetime trauma was associated with reduced mtDNAcn in placenta (β=-0.33; 95%CI -0.63, -0.02). Among women reporting low trauma, increased PM2.5 exposure late in pregnancy (30-38weeks gestation) was significantly associated with decreased mtDNAcn in placenta; no significant association was found in the high trauma group. BDLIMs identified a significant 3-way interaction between PM2.5, maternal trauma, and child sex. Specifically, PM2.5 exposure between 25 and 40weeks gestation was significantly associated with increased placental mtDNAcn among boys of mothers reporting high trauma. In contrast, PM2.5 exposure in this same window was significantly associated with decreased placental mtDNAcn among girls of mothers reporting low trauma. Similar 3-way interactive effects were observed in cord blood. CONCLUSIONS: These results indicate that joint exposure to PM2.5 in late pregnancy and maternal lifetime trauma influence mtDNAcn at the maternal-fetal interface in a sex-specific manner. Additional studies will assist in understanding if the sex-specific patterns reflect distinct pathophysiological processes in addition to mitochondrial dysfunction.
BACKGROUND: Prenatal ambient fine particulate matter (PM2.5) and maternal chronic psychosocial stress have independently been linked to changes in mithochondrial DNA copy number (mtDNAcn), a marker of mitochondrial response and dysfunction. Further, overlapping research shows sex-specific effects of PM2.5 and stress on developmental outcomes. Interactions among PM2.5, maternal stress, and child sex have not been examined in this context. METHODS: We examined associations among exposure to prenatal PM2.5, maternal lifetime traumatic stressors, and mtDNAcn at birth in a sociodemographically diverse pregnancy cohort (N=167). Mothers' daily exposure to PM2.5 over gestation was estimated using a satellite-based spatio-temporally resolved prediction model. Lifetime exposure to traumatic stressors was ascertained using the Life Stressor Checklist-Revised; exposure was categorized as high vs. low based on a median split. Quantitative real-time polymerase chain reaction (qPCR) was used to determine mtDNAcn in placenta and cord blood leukocytes. Bayesian Distributed Lag Interaction regression models (BDLIMs) were used to statistically model and visualize the PM2.5 timing-dependent pattern of associations with mtDNAcn and explore effect modification by maternal lifetime trauma and child sex. RESULTS: Increased PM2.5 exposure across pregnancy was associated with decreased mtDNAcn in cord blood (cumulative effect estimate=-0.78; 95%CI -1.41, -0.16). Higher maternal lifetime trauma was associated with reduced mtDNAcn in placenta (β=-0.33; 95%CI -0.63, -0.02). Among women reporting low trauma, increased PM2.5 exposure late in pregnancy (30-38weeks gestation) was significantly associated with decreased mtDNAcn in placenta; no significant association was found in the high trauma group. BDLIMs identified a significant 3-way interaction between PM2.5, maternal trauma, and child sex. Specifically, PM2.5 exposure between 25 and 40weeks gestation was significantly associated with increased placental mtDNAcn among boys of mothers reporting high trauma. In contrast, PM2.5 exposure in this same window was significantly associated with decreased placental mtDNAcn among girls of mothers reporting low trauma. Similar 3-way interactive effects were observed in cord blood. CONCLUSIONS: These results indicate that joint exposure to PM2.5 in late pregnancy and maternal lifetime trauma influence mtDNAcn at the maternal-fetal interface in a sex-specific manner. Additional studies will assist in understanding if the sex-specific patterns reflect distinct pathophysiological processes in addition to mitochondrial dysfunction.
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