Is lactational sertraline exposure safe for maternal health and the reproductive/neurobehavioral development of the descendants? A study in rats.

Although sertraline is considered one of the safest antidepressants in the lactation period, there are still few studies that assess its impact on child development. Therefore, this experimental study aimed to clarify the effect of sertraline on the neurobehavioral and reproductive development of male rats. Thus, 30 lactating rats were divided into 3 experimental groups (n = 10/group): CO- received filtered water, S10 and S20 groups that received, respectively, 10 and 20 mg/kg/day of sertraline. Treatment was performed by gavage, from postnatal days (PND) 1-20. During this period, the reflex and somatic development of rats were observed, as well as maternal behavior. On PND 21, mothers were euthanized and the organs were weighed. On PND 21, 45, and 100, one male from each litter was euthanized for histological and immunohistochemical (PCNA and WT1) analysis of the reproductive organs. The growth of body weight, the anogenital distance (AGD), the time to puberty, sperm quality, sexual behavior, neurobehavior, and natural fertility were also verified. Statistical analysis: One-way ANOVA or Kruskal-Wallis test (p ≤ 0.05). The results showed that mothers in the S20 group had an increase in thyroid weight. The male offspring exposed to sertraline had lower body weight (PND 7), lower AGD (PND 7 and 14), and delay in reflex development, in addition to histological alterations in the testis (PND 21). In adulthood, sperm quality was altered, without compromising natural fertility. Therefore, the present study found important alterations in the reflex and reproductive development of male rats exposed to sertraline during lactation.

Prenatal exposure to sertraline, associated or not with stress, can negatively program somatic and neurobehavioral development of female rats, and dysregulate reproductive function in adulthood.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed to pregnant women for treating mental illnesses. Among the drugs of this class, sertraline (ST) is the antidepressant therapy recommended most frequently. Therefore, this study aimed to evaluate the impact of gestational ST treatment on reproductive parameters and toxicological target organs of rat female offspring, as well as on somatic, reflex and neurobehavioral development, in a model of maternal adversity. Pregnant Wistar rats received vehicle (filtered water) or ST hydrochloride (20 mg/Kg/day diluted in vehicle) by oral gavage, associated or not with restraint stress for 1 h/day from gestational days 13-20. F1 female offspring was evaluated on reproductive parameters, body weight and somatic and reflex milestones from postnatal day (PND) 1. On PNDs 25 and 72, the elevated-plus-maze test was performed, while toxicological target organs were evaluated on PNDs 42 and 80. In utero exposure to ST, regardless of exposure to stress, reduced body weight at birth and affected the somatic development and estrous cycle. The absolute and relative thyroid weights were increased in Stress/ST group during puberty and adulthood, while the percentage of ovarian structures and the absolute uterine weight were altered in this group on PND 80. Prenatal exposure only to ST reduced initial body weight gain, delayed fur development and increased anxiety-like behavior on PND 25. Thus, this experimental study suggests that intrauterine exposure to ST disrupts the fetal environment and can negatively program serotonin-regulated processes. Furthermore, it impacts thyroid weight when associated with stress.

Rosuvastatin exposure in female Wistar rats alters uterine contractility and do not show evident (anti)estrogenic effects.

Statins are 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor drugs that lead to serum-cholesterol-lowering effects. Rosuvastatin, a third-generation statin, has shown better results in reducing cholesterol concentrations when compared to other widely prescribed statins. Recent studies by our group reported that rosuvastatin impairs reproductive function in rats possibly by disrupting the reproductive-endocrine axis. In this study, we evaluated whether rosuvastatin presents estrogenic or antiestrogenic effects, by an in vivo uterotrophic assay in rats, and investigated the direct effect of this drug upon rat uterine tissue contractility both in non-gravid and gravid periods. Rosuvastatin exposure in vivo at doses of 0 (control), 3, and 10 mg/kg/d was not associated with estrogenic or antiestrogenic effects on uterine tissue. However, in vivo (doses of 0, 3, and 10 mg/kg/d) and ex vivo (concentrations of 0, 1, 10, and 100 µg/mL) exposures to this drug were related to alterations in uterine basal contraction pattern. Furthermore, in vivo and ex vivo rosuvastatin exposures potentially modulate the action of uterine contraction inducers carbachol, norepinephrine, and prostaglandin E2. Thus, rosuvastatin can affect uterine physiology not necessarily by an endocrine mechanism related to the estrogen signaling, but possibly by its pleiotropic effects, with indirect tissue and cellular interactions, since in vivo and ex vivo exposures of uterine fragments to rosuvastatin presented different responses in uterine contractile parameters, which require further studies upon the precise mechanism of action of this drug in female reproductive function.