Universidade Estadual de Londrina (UEL), Brazil.
Universidade Norte do Paraná (UNOPAR), Brazil.
Brain Res Bull. 2018 Sep;142:409-413. doi: 10.1016/j.brainresbull.2018.09.007. Epub 2018 Sep 17.
Fluoxetine (FLX) is an antidepressant from the selective serotonin reuptake inhibitor class that has largely been used for the treatment of depression in pregnancy. However, increasing evidences have indicated the potential of early maternal exposure to FLX to induce molecular and neuro functional effects on the offspring. In the present study we evaluated possible long lasting impacts of the maternal exposure to FLX during gestation and lactation. Female Wistar rats were gavaged with 5 mg/kg of FLX during the period that comprehends the first day of pregnancy (PD0) and the last day of lactation (LD21) (Group FLX). Control group (CTL) received a proportional volume of water. On the postnatal day 75 (PND75), male rats were euthanized and hippocampus, cortex, hypothalamus, and periaqueductal gray area (PAG) were removed. Global DNA methylation was quantified using a high-throughput ELISA-based method. In order to address neuro functional changes animals (PND75) were evaluated in the elevated plus maze and social interaction tests as well as submitted to repeated restraint stress. An increase in the global DNA methylation profile of hippocampus (p = 0.0399) was associated with the early exposure to FLX, whereas no significant change was observed in the hypothalamus (p = 0.6556), cortex (p = 0.9402) or PAG (p = 0.3822). Furthermore, early exposure to FLX was also associated with a reduction in the social interaction time (p = 0.0084) and to a decreased in the plasma corticosterone level when animals were submitted to the restraint stress (p < 0.0001). No significant change in the elevated plus maze test was associated with the early exposure to FLX. In summary, our data demonstrate that maternal exposure to FLX during gestation and lactation results in a long lasting impact on the DNA methylation of hippocampus, and affects the social behavior and the corticosterone response to stress.
氟西汀（FLX）是一种选择性 5-羟色胺再摄取抑制剂类抗抑郁药，主要用于治疗妊娠期间的抑郁症。然而，越来越多的证据表明，母亲在妊娠和哺乳期早期接触 FLX 可能会对后代产生分子和神经功能影响。在本研究中，我们评估了母体在妊娠和哺乳期接触 FLX 可能产生的长期影响。雌性 Wistar 大鼠在妊娠的第一天（PD0）和哺乳期的最后一天（LD21）期间每天灌胃 5mg/kg 的 FLX（FLX 组）。对照组（CTL）接受等量的水。在出生后 75 天（PND75），雄性大鼠被安乐死，取出海马体、皮质、下丘脑和中脑导水管周围灰质区（PAG）。使用高通量 ELISA 法测定全基因组 DNA 甲基化水平。为了评估神经功能变化，对动物（PND75）进行高架十字迷宫和社交互动测试，并进行重复束缚应激。海马体的全基因组 DNA 甲基化谱升高（p=0.0399）与早期接触 FLX 有关，而下丘脑（p=0.6556）、皮质（p=0.9402）或 PAG（p=0.3822）未观察到显著变化。此外，早期接触 FLX 还与社交互动时间减少（p=0.0084）和束缚应激时血浆皮质酮水平降低（p<0.0001）有关。早期接触 FLX 与高架十字迷宫试验无显著变化相关。综上所述，我们的数据表明，母体在妊娠和哺乳期接触 FLX 会对海马体的 DNA 甲基化产生长期影响，并影响社交行为和应激时皮质酮的反应。
