In Utero and Lactational Exposure to Fluoxetine in Wistar Rats: Pregnancy Outcomes and Sexual Development

Abstract

This study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/ day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and oestrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Oestrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine were observed. Finally, pup birthweight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic-like doses.Major depressive disorder is one of the most widespread and debilitating forms of mental illness, characterized by behavioural, affective, cognitive and somatic symptoms [1]. Epidemiological studies have shown that, in women, depression is the major cause of disease-related disability worldwide [2], with an increased prevalence during reproductive age, especially during pregnancy (10%) and after childbirth (20%) [3,4].The past decade has seen a large increase in the use of selective serotonin reuptake inhibitor (SSRI) antidepressants during pregnancy and lactation. Among these, fluoxetine was the most widely used antidepressant during pregnancy [5,6]. In this context, it is important to consider that fluoxetine crosses the placenta [7], reaching similar levels in maternal and foetal serum. In addition, fluoxetine is also secreted into breast milk during lactation [8,9]. The possibility of perinatal exposure to fluoxetine has raised significant concerns about its possible adverse effects in mothers and infants. The pre-and early post-natal development of the reproductive system is under complex integrative control of the central nervous system, pituitary, gonads and genital tract, all of which are potential targets of transplacental and lactational chemical exposure [10]. Therefore, understanding the effects of fluoxetine on the reproductive system of the developing foetus/neonate and pregnant and nursing women is important.Investigations of the negative consequences of SSRI antidepressants during pregnancy and lactation are promising, but still with a lack of significant information on the spectrum of adverse effects and mode of action of these substances at different stages of animal and human development. According to the review by Ellfolk and Malm [11], clinical studies have revealed l...

Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

“…In the present study we have shown that fetal and neonatal exposure to fluoxetine resulted in a significant increase in body weight in the female but not in the male offspring; these changes occurred in the absence of altered postnatal food consumption despite the fact that fluoxetine has been shown to affect food consumption in adult rodents (Lauzurica et al, 2013). Moreover, although other experiments in rats have reported a reduction in birth weight following fluoxetine exposure during pregnancy (de Oliveira et al, 2013;Müller et al, 2013) we did not observe any effect of fluoxetine in altering birth weight in our study, suggesting that the metabolic deficits in this model are independent of impaired fetal growth. Although the mechanism(s) underlying the sex-specific differences in body composition are unknown, sex-specific differences in the long-term effects of prenatal exposure to SSRIs and childhood overweight have also been reported in human studies (Grzeskowiak et al, 2013).…”

Long-Term Outcomes of Developmental Exposure to Fluoxetine: A Review of the Animal Literature

“…In one study, exposure to FLX from mid-to-late gestation in rats caused pulmonary hypertension and structural abnormalities of the heart and pulmonary vascular system, coinciding with an increase in postnatal mortality from 0 in controls to 15% in exposed pups [18]. A similar increase was noted by Vorhees et al [19] following prenatal exposure, and by Müller et al [20] following administration of a high dose of FLX to the dam from 1 week after conception to weaning, though lower doses did not have the same effect. In neither study was the cause of this increased mortality examined.…”

“…Finally, sexual differentiation during early life may also be altered, as postnatally exposed male (but not female) rats were found to have shorter than normal anogenital distances at 3 weeks of age, though serum testosterone was not altered, and the difference in anogenital distance was no longer apparent by adulthood in males [26]. In another study, prenatal exposure to low and high doses of FLX was found to have no effect on anogenital distance at birth [20]. …”

“…However, it is worth noting that such findings are often difficult to interpret, as the effect of FLX exposure can be confounded by the effect of maternal depression, which itself might increase the risk of premature birth [30]. Maternal condition is more easily controlled for in studies of non-human animals, some of which have found that FLX has a deleterious effect on one or more measures, including decreased pregnancy duration [22], litter size [11,31] and birth weight [19,20,22,23,24,32]. However, as with the clinical research, for each of these factors there are multiple studies that report no significant alterations, even using similar dosages and periods of exposure (table 1).…”

Perinatal selective serotonin reuptake inhibitor (SSRI) effects on body weight at birth and beyond: A review of animal and human studies

“…Other studies have found mixed results, with reduced weight: at birth, but not at pre-weaning and during adulthood [42]; at pre-weaning, but not at the juvenile stage [49]; and at pre-weaning, but no difference at the juvenile stage and adulthood [42,47]. Perinatal SSRIs studies have also revealed sex differences at adulthood with reduced weight in males compared to control males (no difference in females; 44; 45, 85] and another study found reduced weights at different time points for males and female rodents (see Table 1 for details) [87].…”