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

Abstract

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.

Fine particulate matter (PM2.5) inhalation-induced alterations in the plasma lipidome as promoters of vascular inflammation and insulin resistance

“…One possibility is that circulating cytokines could contribute to vascular injury caused by CAP; however, in past studies, we have not found changes in circulating cytokines such as TNF-α and IL-6 in the plasma from CAP-exposed mice ( 20 ). In contrast, our studies and investigations by others indicate that PM 2.5 exposure increases local inflammation in vascular and cardiac tissue ( 10 , 19 ). Another possibility is that circulating microparticles or exosomes could deliver cargo to the vasculature that contributes to pathology; few published reports have addressed this possibility ( 23 , 61 , 62 ).…”

“…Acute PM 2.5 exposure increases the risk of myocardial infarction, arrhythmias, and stroke (2), whereas chronic exposure contributes to the development of hypertension, atherosclerosis, and diabetes (2,(4)(5)(6). In utero and early life exposure is associated with cardiac dysfunction and the induction of transcriptional as well as metabolic changes in cardiomyocytes (7)(8)(9)(10). Because PM 2.5 exposure affects several aspects of CVD, it is likely that it alters processes that are common to several manifestations of CVD.…”

An Overview of Adverse Outcome Pathway Links between PM2.5 Exposure and Cardiac Developmental Toxicity

“…Furthermore, exposure to PM 2.5 via air cell injection resulted in elevated heart rate and thickened right ventricular wall thickness in fertile chicken eggs . Abnormalities in cardiac structure and function in the offspring induced by PM 2.5 exposure during pregnancy were confirmed in FVB mice and Wistar rats. , Maternal exposure to PM 2.5 during pregnancy damaged offspring hearts and changed cardiovascular development-related genes in C57BL/6 mice …”

Cardiovascular adaptations to particle inhalation exposure: molecular mechanisms of the toxicology

“…Calcium-regulated contraction is significantly affected throughout development in progeny exposed to particulate matter during gestation. Assessment of 14-day-old progeny whose dams were exposed to PM 2.5 during gestation revealed decreased cardiomyocyte contractility through calcium dynamics, with changes to proteins involved in calcium flux in the heart, SERCA-2a, p-PLN, Na ϩ /Ca 2ϩ exchanger (NCX), calcium channel, voltage-dependent L type, and ␣1C subunit (CaV1.2) (149,150). Offspring whose dams were exposed during gestation also present with major cardiac anomalies present into adulthood as a result of ENM-induced mitochondrial dysfunction.…”