In utero exposure to fine particulate matter results in an altered neuroimmune phenotype in adult mice

Background/Aims: Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particulate matter (PM2.5) exposure in utero causes hypertension in the offspring, but the exact mechanisms are not clear. Renal dopamine D1 receptor (D1R), regulated by G protein-coupled receptor kinase type 4 (GRK4), plays an important role in the regulation of renal sodium transport and blood pressure. In this present study, we determined if renal D1R dysfunction is involved in PM2.5–induced hypertension in the offspring. Methods: Pregnant Sprague–Dawley rats were given an oropharyngeal drip of PM2.5 (1.0 mg/kg) at gestation day 8, 10, and 12. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of GRK4 and D1R were determined by immunoblotting. The phosphorylation of D1R was investigated using immunoprecipitation. Plasma malondialdehyde and superoxide dismutase levels were also measured in the offspring. Results: As compared with saline-treated dams, offspring of PM2.5-treated dams had increased blood pressure, impaired sodium excretion, and reduced D1R-mediated natriuresis and diuresis, accompanied by decreased renal D1R expression and GRK4 expression. The impaired renal D1R function and increased GRK4 expression could be caused by increased reactive oxidative stress (ROS) induced by PM2.5 exposure. Administration of tempol, a redox-cycling nitroxide, for 4 weeks in the offspring of PM2.5-treated dam normalized the decreased renal D1R expression and increased renal D1R phosphorylation and GRK4 expression. Furthermore, tempol normalized the increased renal expression of c-Myc, a transcription factor that regulates GRK4 expression. Conclusions: In utero exposure to PM2.5 increases ROS and GRK4 expression, impairs D1R-mediated sodium excretion, and increases blood pressure in the offspring. These studies suggest that normalization of D1R function may be a target for the prevention and treatment of the hypertension in offspring of mothers exposed to PM2.5 during pregnancy.

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Abstract 17375: In Utero Particulate Matter Exposure Produces Heart Failure and Electrical Remodeling at Adulthood

Circulation ◽

10.1161/circ.132.suppl_3.17375 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Victor P Long ◽

Vineeta Tanwar ◽

Matthew W Gorr ◽

Stephen H Baine ◽

Ingrid M Bonilla ◽

...

Keyword(s):

Particulate Matter ◽

Cardiac Dysfunction ◽

Systolic Function ◽

In Utero ◽

In Utero Exposure ◽

Electrical Remodeling ◽

Morphological Alterations ◽

Adult Mice ◽

Significant Prolongation ◽

Electrophysiological Recordings

Introduction: In utero exposure to particulate matter through perinatal development has been demonstrated to produce cardiac dysfunction during adulthood. It is unknown what effect exposure to air pollution during the in utero period alone has on cardiac dysfunction and electrical remodeling in adulthood. We tested the hypothesis that adult mice exposed to concentrated particulate matter in utero would demonstrate global cardiac dysfunction as well as cellular electrical remodeling at adulthood. Methods: Female FVB mice were exposed either to filtered air (FA) or particulate matter with diameter less than 2.5 μm (PM2.5) at a concentration of ~ 51.69 μg/m3 for 6 h/day, 7 days/wk (consistent with exposure in a large metropolitan city) beginning at plug formation throughout pregnancy. Cardiac function was assessed via ECHO in male offspring at 12 wks of age, followed by sacrifice and isolation of ventricular cardiomyocytes from both groups of mice for electrophysiological recordings. Results: ECHO identified increased LVESd (2.25 ± 0.20 FA, 2.61 ± 0.35 PM2.5, P=0.0001) and LVEDd (3.89 ± 0.03 FA, 3.99 ± 0.038 PM2.5, P=0.04) dimensions and reduced PWTs (1.40 ± 0.05 FA, 1.26 ± 0.04 PM2.5, P=0.04) in mice exposed in utero to PM2.5. Morphological alterations were associated with lower systolic function as indicated by reduced fractional shortening% (43.6 ± 2.1 FA, 33.2 ± 1.6 PM2.5, P=0.0009) in PM2.5 exposed mice compared to FA controls. Electrophysiological recordings revealed significant prolongation of the action potential at 90% repolarization (APD90) in PM2.5 exposed mice compared to FA. (FIGURE) Conclusions: In utero exposure to relevant levels of particulate matter results in dilated cardiomyopathy and electrical remodeling. Future studies are warranted to determine the causes of, and the exposure thresholds resulting in this adverse cardiac remodeling.

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