Abstract
This study examines sex-specific effects of developmental sertraline exposure on cardiac function and gene expression before and after myocardial infarction (MI) in mice. Female C57BL/6 mice (10 weeks) received intraperitoneal sertraline (5 mg/kg/day, n = 37) or saline (n = 20) before mating, during pregnancy, and postnatally to pups (1.5 mg/kg/day, postnatal Days 0-14). MI in offspring was induced at 10 weeks by left coronary artery ligation. Randomly chosen offspring (sham n = 8 and MI n = 26 per sex) underwent baseline echocardiography and at 10 weeks post-MI if surviving. Serotonin- and estrogen-related gene expression was analyzed. Before MI, sertraline-exposed females had lower heart rate (649.1 ± 102.0 vs. 692.9 ± 38.4 bpm, n = 34), increased end-systolic volume, and reduced ejection fraction (80.7 ± 6.3% vs. 83.9 ± 3.5%; p < 0.05). Exposed males also had lower heart rates (665.9 ± 32.7 vs. 683.3 ± 47.9 bpm, n = 34, p < 0.05). Post-MI, both sexes remodeled similarly (scar size, ischemic-zone fraction); sertraline-exposed males had higher scar-zone collagen (p < 0.05) and a nonsignificant lower survival trend than females. Sertraline altered serotonin-related gene expression (Htr2a, Htr2b, Slc6a4), particularly in male sham mice. Developmental sertraline exposure induces sex-specific cardiac changes, potentially affecting post-MI outcomes, with males showing more structural and survival impairments.
Keywords:
cardiac function; developmental exposure; myocardial infarction; serotonin receptors; sertraline; sex‐specific effects.