Cardiac Outcomes After Perinatal Sertraline Exposure in Mice

Abstract

Selective serotonin reuptake inhibitors are prescribed to 6%-10% of pregnant women in the United States. Using an intrauterine plus neonatal exposure model to represent exposure throughout human pregnancy, we hypothesized sertraline exposure would impact intracardiac serotonin signaling and lead to small left heart syndrome in the absence of maternal psychopathology. C57BL/6 adult female mice received sertraline (5 mg·kg·d IP) or saline throughout pregnancy to time of delivery. Pups maintained exposure on postnatal days 1-14 to encompass the developmental window analogous to human gestation. Sertraline-exposed mice had increased cardiac hydroxyproline content, decreased 5-HT2B receptor mRNA levels, and increased 5-HT2A receptor and serotonin transporter mRNA levels on postnatal day 21 (P < 0.05). These changes were associated with diminished exercise capacity at 6 weeks (P < 0.05) and decreased adult shortening fraction and stroke volume at 5 months. Isolated cardiomyocytes from neonatal sertraline-exposed mice had significantly decreased proliferation, cross-sectional area, and phosphorylation of Akt (P < 0.05 vs. neonatal control mice). Perinatal sertraline exposure alters neonatal cardiac development and produces long-standing changes in adult cardiac function and exercise capacity. Further studies are needed to assess whether similar findings are present in the growing population that has been exposed to selective serotonin reuptake inhibitors during development.

Figure 1

Subgross photomicrographs of the hearts from mice treated with sertaline (A) and saline (C) and stained with Masson’s trichrome to highlight collagen. Bars = 1 mm. Higher magnificantion of the black boxes in sertraline-exposed heart (B) and saline exposed heart (D). Bar = 100 μm.

Figure 2

Quantification of (A) intracardiac hydroxyproline content (N= 9 saline, 10 sertraline) and intracardiac mRNA levels of the (B) 5-HT_2B receptor, (C) 5-HT_2A receptor, and (D) serotonin transporter (5-HTT) on postnatal day 21 (N=15 saline, 16 sertraline). *P<0.05 compared to controls, **P<0.01 compared to controls.

Figure 3

A representative sample of 5-HT_2B receptor expression in left ventricular tissues from sertraline-exposed mice (Ser) and control mice (Sal) as determined by Western blot.

Figure 4

Total exercise distance measured during exhaustion tests for mice at 6, 8, 10, 15 and 20 weeks of age. Exercise distance is defined as total distance completed on treadmill with gradually increased incline and speed. N=11 saline, 12 sertraline. *P<0.05 compared to controls.

Figure 5

Quantification from western blots of phosphorylated to total Akt (A) and phosphorylated to total ERK (C) in 2–4 day old isolated cardiomyocytes from control and sertraline-exposed mice at baseline and after stimulation with 5-HT (B,D). N= 11 saline, 8 sertraline. *p<0.05 compared to controls.

Figure 6

Confocal microscopy of isolated cardiomyocytes from saline exposed (top) and sertraline-exposed (bottom) mice. Panels show myomesin stain (red), DAPI stain (blue), EdU stain (green), and merged image.