Could maternal exposure to the antidepressants fluoxetine and St. John's Wort induce long-term reproductive effects on male rats?

Vieira, Milene Leivas; Hamada, Renata Yumi; Gonzaga, Natalia Ignácio; Bacchi, André Demambre; Barbieri, Mainara Ferreira; Moreira, Estefânia Gastaldello; Mesquita, Suzana de Fátima Paccola; Gerardin, Daniela Cristina Ceccatto

doi:10.1016/j.reprotox.2012.07.006

Cited by 37 publications

(27 citation statements)

References 39 publications

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“…In adolescence, early exposure inhibits locomotion [23,41,50,51] and decreases novel object exploration [52]. Lisboa et al [35] observed decreased locomotion only in male mice, suggesting a difference in sensitivity between the sexes.…”

Section: Long-term Behavioural Outcomesmentioning

confidence: 99%

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

2013

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During and following pregnancy, women are at high risk of experiencing depression, for which fluoxetine (FLX; brand names Prozac, Sarafem, Rapiflux) is the most commonly prescribed treatment. An estimated 1.4-2.1% of pregnant women use this medication, which inhibits the reuptake of serotonin and thereby increases serotonergic activity at the synapse. Serotonin acts as a cue guiding numerous neurodevelopmental processes, and changes in the concentration of serotonin can disrupt normal in utero brain development and organization in humans and other animals, thus providing a mechanism by which maternal intake of FLX might alter neural development and ultimately behaviour. Despite this possibility, long-term alterations of behaviour and the brain have not been well studied in individuals exposed to FLX during pregnancy or soon after birth, perhaps because conducting such studies beyond infancy presents significant challenges. To remedy this problem, many researchers have turned to modelling the effects of developmental FLX exposure in non-human animals, primarily rodents. The body of literature on this topic has expanded considerably over the past several years, yet a comprehensive review is lacking. In order to fill this gap, we have summarized the findings of those studies describing the long-term behavioural and neurophysiological effects of FLX exposure in non-human animals in early development. We also discuss methodological considerations and common shortcomings of research in this area. The precise nature of the long-term effects of developmental FLX exposure remains difficult to specify, as these effects appear to be highly variable and dependent on numerous factors. Overall, however, it is clear that early FLX exposure in non-human animals can alter the development of the brain in ways that are relevant to behaviour in adulthood, decreasing exploration and social interaction, and in some cases altering anxiety- and depression-like behaviours.

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Section: Long-term Behavioural Outcomesmentioning

confidence: 99%

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

2013

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“…Cada, Hansen, LaBorde, and Ferguson () investigated the effect of various doses of SJW in groups of Sprague–Dawley rats, measuring whole and regional brain weights and investigating behaviour again using Morris maze tasks, among other assessment. M. L. Vieira, Hamada, et al () also worked with Wistar rats in their study of effects of fetal exposure to SJW or fluoxetine and assessed reproductive physiology and various behaviour in male pups. The same research group used fluorescence imaging to measure hypericin levels in maternal and fetal tissue samples, the behaviour of exposed dams post‐parturition and male offspring using models that assess anxiety and depression (Campos, Guerra, Peters, & E Sá, ; V. A. Vieira, Campos, et al, ).…”

Section: Resultsmentioning

confidence: 99%

The safety of St John's wort (Hypericum perforatum) in pregnancy and lactation: A systematic review of rodent studies

Avila

Whitten

Evans

2018

Phytotherapy Research

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Herbal products are popular among women during the perinatal period. St John's wort (SJW), Hypericum perforatum, is a common remedy for mild depression, a problem prevalent in this population. Although the safety of herbal products must be investigated, ethical issues constrain intervention studies in humans. Hence, animal studies often inform clinical decisions. The objective of this study is to systematically review rodent studies assessing the safety of SJW during the perinatal period. A literature search to November 10, 2017, identified 10 rodent studies that met a priori inclusion criteria. Study quality was evaluated according to both the Systematic Review Centre for Laboratory animal Experimentation tool for assessing bias and recommendations for appropriate reporting of herbal medicine research. Significant methodological limitations were found in each of the studies reviewed. These limitations include the lack of botanical verification and omission of extract characterization, inadequate explanation of dosage rationale, and absence of bias limiting protocols. Critical appraisal with contemporary tools indicates that each of the reviewed studies lacks appropriate rigour, rendering the results unreliable. Despite this, these papers are used in the rationale for recommending or contraindicating SJW during pregnancy and lactation.

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“…This may be due to the long time that the animals were not exposed to fluoxetine between puberty and adulthood. In addition, other studies also showed changes in spermatogenesis of rats even after a long period of time at doses of 5, 7.5, and 10 mg/kg of fluoxetine [Silva Junior et al 2013;Vieira et al 2013]. Therefore, doses above 5-10 mg/kg of fluoxetine should be considered carefully as they may represent a risk to the fertility of male rats.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, doses above 5-10 mg/kg of fluoxetine should be considered carefully as they may represent a risk to the fertility of male rats. Fluoxetine prescription in humans ranges from 20-80 mg/day, corresponding to 0.29-1.14 mg/kg [Vieira et al 2013]. However, we should consider that rats are more resistant to drugs than humans; according to Aggarwal et al [2012], 10 mg/kg fluoxetine is a mild dose and 20 mg/kg is a moderate dose for rats.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine induces changes in the testicle and testosterone in adult male rats exposed via placenta and lactation

Filho

Torres

Amorim

et al. 2014

Systems Biology in Reproductive Medicine

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Fluoxetine is a selective serotonin reuptake inhibitor used to treat depression in pregnant and nursing women. However, recent studies have shown adverse effects in the male reproductive system after fluoxetine treatment. Aiming to analyze the extent of damage caused by fluoxetine in the testicle and safe doses for treatment during the perinatal period, the present study analyzed the effects of in utero exposure and exposure during lactation to fluoxetine in spermatogenesis of male rat offspring in adulthood. Wistar rat dams were orally treated with fluoxetine (5, 10, and 20 mg/kg) from 13 days of gestation to lactation day 21 and their offspring were analyzed at 90 days old. Results showed a reduction in the weight of testes (16%), epididymis (28%), and seminal glands (18%) in animals exposed to fluoxetine 20 mg/kg compared to the control. Seminal gland weight was also reduced 25% and 30% in animals exposed to 5 mg/kg and 10 mg/kg fluoxetine, respectively. Body weight of animals exposed to 20 mg/kg fluoxetine was reduced from post-natal day 9 to 36 compared to controls but from the post-natal day 9 to 36 there was no statistical difference. The volume of seminiferous epithelium reduced 17% and the total volume of Leydig cells reduced 30% in the group exposed to fluoxetine at 20 mg/kg. Furthermore, Leydig cells volume reduced 29% in the 5 mg/kg group. The length of the seminiferous tubules reduced 17% and daily sperm production per testicle also reduced 18% in animals exposed to the highest dose of fluoxetine compared to controls. The individual area of Leydig cells increased 7% and plasma testosterone increased 49% in animals exposed to fluoxetine at 20 mg/kg. In conclusion, exposure to 20 mg/kg fluoxetine via the placenta and during lactation may change testosterone and testicular parameters important for sperm production and male fertility in adulthood.

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Could maternal exposure to the antidepressants fluoxetine and St. John's Wort induce long-term reproductive effects on male rats?

Cited by 37 publications

References 39 publications

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

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

The safety of St John's wort (Hypericum perforatum) in pregnancy and lactation: A systematic review of rodent studies

Fluoxetine induces changes in the testicle and testosterone in adult male rats exposed via placenta and lactation

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