In Utero Particulate Matter Exposure Produces Heart Failure, Electrical Remodeling, and Epigenetic Changes at Adulthood

Tanwar, Vineeta; Gorr, Matthew W.; Velten, Markus; Eichenseer, Clayton; Long, Victor P.; Bonilla, Ingrid M.; Shettigar, Vikram; Ziolo, Mark T.; Davis, Jonathan P.; Baine, Stephen; Carnes, Cynthia A.; Wold, Loren E.

doi:10.1161/jaha.117.005796

Cited by 53 publications

(38 citation statements)

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“…Increased expression of DNMT1 has been reported in lungs of C57BL/6 mice exposed to concentrated ambient PM 2.5 at a level of 5.5 × 10 5 particle/cm 2 (Soberanes et al, 2012). In mice prenatally exposed to 73.61 μg/m 3 of ambient PM 2.5 for 5 h/day, increased expression of DNMT1, DNMT3a, and DNMT3b were detected in adult heart samples (Tanwar et al, 2017). The finding of an increased expression of DNMT1 suggested potential alterations of DNA methylation in DE-exposed neonatal pups.…”

Section: Discussionmentioning

confidence: 95%

Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6

Chang

Daza²,

Hevner

et al. 2019

Brain, Behavior, and Immunity

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Several epidemiological studies have shown associations between developmental exposure to traffic-related air pollution and increased risk for autism spectrum disorders (ASD), a spectrum of neurodevelopmental disorders with increasing prevalence rate in the United States. Though animal studies have provided support for these associations, little is known regarding possible underlying mechanisms. In a previous study we found that exposure of C57BL/6J mice of both sexes to environmentally relevant levels (250-300 μg/m 3) of diesel exhaust (DE) from embryonic day 0 to postnatal day 21 (E0 to PND21) caused significant changes in all three characteristic behavioral domains of ASD in the offspring. In the present study we investigated a potential mechanistic pathway that may be of relevance for ASD-like changes associated with developmental DE exposure. Using the same DE exposure protocol (250-300 μg/m 3 DE from E0 to PND21) several molecular markers were examined in the brains of male and female mice at PND3, 21, and 60. Exposure to DE as above increased levels of interleukin-6 (IL-6) in placenta and in neonatal brain. The JAK2/STAT3 pathway, a target for IL-6, was activated by STAT3 phosphorylation, and the expression of DNA methyltransferase 1 (DNMT1), a STAT3 target gene, was increased in DEexposed neonatal brain. DNMT1 has been reported to down-regulate expression of reelin (RELN), an extracellular matrix glycoprotein important in regulating the processes of neuronal migration. RELN is considered an important modulator for ASD, since there are several polymorphisms in this gene linked to the disease, and since lower levels of RELN have been reported in brains of *

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Section: Discussionmentioning

confidence: 95%

Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6

Chang

Daza²,

Hevner

et al. 2019

Brain, Behavior, and Immunity

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“…In our previous work, we demonstrated the role of PM 2.5 exposure during developmental periods in influencing an adult disease phenotype 14 , however, it did not determine whether PM 2.5 exposure during the in utero period is equally detrimental to neonatal cardiac function. Here, we hypothesized that PM 2.5 in utero exposure can influence cardiac function in neonatal mice (14 day old).…”

Section: Introductionmentioning

confidence: 87%

PM 2.5 exposure in utero contributes to neonatal cardiac dysfunction in mice

Tanwar

Adelstein

Grimmer

et al. 2017

Environmental Pollution

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Objective Exposure of fine particulate matter (PM2.5) to pregnant dams has been shown to be strongly associated with adverse cardiovascular outcomes in offspring at adulthood, however, effects evident during neonatal periods are unclear. We designed this study to examine cardiac function of neonatal mice (14 days old) exposed to in utero PM2.5. Methods Pregnant FVB female mice were exposed either to filtered air (FA) or PM2.5 at an average concentration of 91.78 μg/m3 for 6h/day, 5 days/wk (similar to exposure in a large industrial area) throughout the gestation period (20 days). After birth, animals were analyzed at day 14 of life. Results Fourteen day old mice exposed to PM2.5 during in utero period demonstrated decreased fractional shortening (%FS, 41.1±1.2% FA, 33.7±1.2% PM2.5, p<0.01) and LVEDd (2.87±0.08 mm FA, 2.58±0.07 mm PM2.5, p<0.05) compared to FA exposed mice. Contractile kinetics and calcium transients in isolated cardiomyocytes from PM2.5 exposed mice illustrated reduced peak shortening (%PS, 16.7±0.5% FA, 14.7±0.4% PM2.5, p<0.01), negative contractile velocity (- dL/dT, -6.91±0.3 μm/s FA, -5.46±0.2 μm/s PM2.5, p<0.001), increased time to relaxation 90% (TR90, 0.07±0.003 s FA, 0.08±0.004 s PM2.5, p<0.05), decreased calcium transient amplitude (Δ340/380, 33.8±3.4 FA, 29.5±2.8 PM2.5) and slower fluorescence decay rate (τ, 0.72±0.1 s FA, 1.16±0.15 s PM2.5, p<0.05). Immunoblotting studies demonstrated alterations in expression of Ca2+ handling proteins- SERCA-2A, p-PLN, NCX and CaV1.2 in hearts of 14 day old in utero PM2.5 exposed mice compared to FA exposed hearts. Conclusion PM2.5 exposure during the critical in utero period adversely affects the developing mouse fetus leading to functional cardiac changes that were evident during the very early (14 days) stages of adolescence. These data demonstrated that exposure to PM2.5 during the gestation period significantly impacts cardiovascular outcomes early in life.

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“…Epidemiological studies have also linked PM 2.5 with increased risk for cardiovascular disease in humans, including hypertension, stroke, heart failure, atherosclerosis, myocardial ischemia, arrhythmias, and enhanced thrombosis (22). In addition, exposure of gestating mice to elevated mass concentrations of PM 2.5 during gestation altered cardiac structure (i.e., increased left ventricular end-systolic and diastolic diameters, reduced left ventricular posterior wall thickness, and reduced end-systolic elastance) and blunted contractility (e.g., blunted contractile response to β-adrenergic stimulation) (23). Our study shows that offspring from the PA dams exhibit impairment in the NOmediated vasodilatory response of their aortas to acetylcholine (Fig.…”

Section: Discussionmentioning

confidence: 99%

Adverse organogenesis and predisposed long-term metabolic syndrome from prenatal exposure to fine particulate matter

Brown

Zamora

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Exposure to fine particulate matter (PM) during pregnancy is associated with high risks of birth defects/fatality and adverse long-term postnatal health. However, limited mechanistic data are available to assess the detailed impacts of prenatal PM exposure. Here we evaluate fine PM exposure during pregnancy on prenatal/ postnatal organogenesis in offspring and in predisposing metabolic syndrome for adult life. Between days 0 and 18 of gestation, two groups of adult female rats (n = 10 for each) were placed in a dualexposure chamber device, one with clean ambient air (∼3 μg·m −3 ) and the other with ambient air in the presence of 100 to 200 μg·m −3 of ultrafine aerosols of ammonium sulfate. At birth (postnatal day 0, PND0), four males and four females were selected randomly from each litter to be nursed by dams, whereas tissues were collected from the remaining pups. At PND21, tissues were collected from two males and two females, whereas the remaining pups were fed either a high-or low-fat diet until PND105, when tissues were obtained for biochemical and physiological analyses. Maternal exposure to fine PM increased stillbirths; reduced gestation length and birth weight; increased concentrations of glucose and free fatty acids in plasma; enhanced lipid accumulation in the liver; and decreased endothelium-dependent relaxation of aorta. This lead to altered organogenesis and predisposed progeny to long-term metabolic defects in an age-, organ-, and sex-specific manner. Our results highlight the necessity to develop therapeutic strategies to remedy adverse health effects of maternal PM exposure on conceptus/postnatal growth and development.air pollution | pregnancy outcomes | postnatal health | metabolism W ith increasing urbanization, industrialization, and economic growth among developing/developed countries worldwide, air pollution has emerged as one of the greatest public health epidemics in the 21st century (1-5). According to the World Health Organization, 9 in 10 people breathe air containing high levels of pollutants, and one in nine of the global deaths is attributed to exposure to air pollution, reaching over total 7 million premature deaths each year (4, 5). Air pollution represents an environmental problem not only in developing countries but also in developed countries. For example, despite major progress made to improve air quality in the United States, ∼111 and 53 million people nationwide still inhabited places with pollutant levels exceeding the National Ambient Air Quality Standards and above the annual and/or 24-h particulate matter (PM) standard, respectively, in 2017 (6). There is accumulating evidence that several critical events in embryonic development during pregnancy are compromised by air pollution. Epidemiological studies have shown that maternal exposure to fine PM (particles with an aerodynamic diameter small than 2.5 μm, PM 2.5 ) is associated with high risks for preterm births, low birth weights, stillbirths, and adverse postnatal health conditions that include both pulmonary and nonp...

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In Utero Particulate Matter Exposure Produces Heart Failure, Electrical Remodeling, and Epigenetic Changes at Adulthood

Cited by 53 publications

References 53 publications

Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6

Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6

PM 2.5 exposure in utero contributes to neonatal cardiac dysfunction in mice

Adverse organogenesis and predisposed long-term metabolic syndrome from prenatal exposure to fine particulate matter

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