Desenvolvimento e performance reprodutiva da prole feminina de ratas Wistar expostas à sertralina associada ou não ao estresse na gestação ou na lactação.
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Data
2022-05-27
Autores
Moura, Mayara Silva [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
Os inibidores seletivos de recaptação de serotonina (ISRS) são os medicamentos de escolha para mulheres com quadros depressivos nos períodos gestacional e lactacional. No entanto, o uso desses antidepressivos nos períodos pré e pós-parto tem sido correlacionado com diversas alterações na prole em animais e humanos. A sertralina (ST) é um dos ISRSs mais usados na gestação e na lactação, mas pouco se sabe sobre o impacto da sua utilização nestes períodos, especialmente em relação à prole feminina. Assim, o objetivo do presente trabalho foi avaliar os efeitos da exposição gestacional (associada ou não ao estresse) ou lactacional à ST sobre o desenvolvimento somático, de reflexos, neucomportamental e reprodutivo da prole feminina de ratas Wistar. Na exposição gestacional, ratas Wistar prenhes receberam ST (20 mg/Kg/dia diluída em veículo) via gavagem associada ou não a estresse de contenção por 1 h/dia nos dias gestacionais 13 ao 20 (n=7-10). Na exposição lactacional, ratas Wistar lactantes foram tratadas com a ST (10mg/Kg/dia e 20mg/Kg/dia diluída em veículo) via gavagem durante toda a lactação (n=9/10). O peso corpóreo das mães e o consumo de ração no período de tratamento foram avaliados no experimento da exposição lactacional. Em ambos os experimentos, a prole feminina foi avaliada quanto ao peso corpóreo, ganho de peso e marcos do desenvolvimento somático e de reflexos. O teste do labirinto em cruz elevado foi realizado na prole jovem e adulta em ambos os experimentos. Foram avaliados os seguintes parâmetros do desenvolvimento e da função reprodutiva: distância ano-genital, instalação da puberdade, ciclo estral, peso de órgãos genitais, histomorfometria do útero e do ovário das ratas púberes e adultas, comportamento sexual e teste de fertilidade. Os resultados foram comparados entre os grupos pelos testes paramétricos ANOVA two-way (para o experimento realizado durante a gravidez) e ANOVA one-way (para o experimento realizado durante a lactação) seguidos pelos testes de Tukey, e pelos testes não paramétricos Kruskal-Wallis seguido pelo teste de Dunn ou teste do Chi-quadrado. As diferenças foram consideradas estatisticamente significativas quando p ≤ 0,05. A exposição in utero à ST, independente da exposição ao estresse, reduziu o peso corpóreo ao nascimento, atrasou a erupção dos incisivos, aumentou o peso absoluto das tireoides no dia pós-natal (DPN) 80 e alterou o ciclo estral das ratas. A exposição à ST combinada ao estresse também provocou aumento no peso absoluto e relativo das tireoides no DPN 42, além de aumentar o peso relativo das tireoides, o peso absoluto do útero e a porcentagem de estruturas ovarianas DPN 80. No grupo ST, também foi observado peso corpóreo reduzido no DPN 21, menor ganho de peso no período pré-desmame, atraso no aparecimento de pelos e aumento do comportamento relacionado à ansiedade na prole jovem. O tratamento com a ST durante a lactação não alterou o peso corpóreo materno ou o consumo de ração. A exposição lactacional à maior dose de ST reduziu o peso corpóreo no DPN 7, enquanto ambos os grupos tratados apresentam pesos corpóreos reduzidos no DPN 21. No grupo tratado com a maior dose de ST, também foram observadas adrenais e hipófises com maiores pesos relativos no DPN 21. O grupo tratado com a dose de 10 mg/Kg apresentou atraso na ocorrência do primeiro estro e redução no peso absoluto da hipófise no DPN 42. Ambos os grupos expostos à ST apresentaram redução na altura do endométrio no DPN 75 e aumento nos pesos relativos das tireoides no DPN 42, embora apenas o grupo tratado com a maior dose tenha apresentado tireoides aumentadas no DPN 75. Conclui-se que o tratamento com ST, nessas condições experimentais, teve repercussões em parâmetros reprodutivos, no crescimento inicial, no peso das tireoides, na maturação somática e no desenvolvimento neurocomportamental e de reflexos da prole feminina de ratas, o que levanta o questionamento em relação a segurança da utilização desse antidepressivo na clínica humana nos períodos gestacional e lactacional.
The selective serotonin reuptake inhibitors (SSRIs) are the medications of choice for depressive women during gestation e lactation. However, the use of these antidepressants in the pre and postpartum periods has been correlated with several changes in offspring in animals and humans. Sertraline (ST) is one of the most used SSRIs in pregnancy and lactation, but little is known about the impact of its use in these periods, especially in relation to female offspring. Thus, the aim of the present study was to evaluate the effects of gestational (associated or not with stress) and lactational exposure to ST on the somatic, reflex, neurobehavioral and reproductive development of female offspring of Wistar rats. In gestational exposure, pregnant Wistar rats received ST (20 mg/Kg/day diluted in vehicle) by oral gavage associated or not with restraint stress for 1 h/day from gestational days 13 to 20 (n=7-10). In lactational exposure, lactating Wistar rats were treated with ST (10mg/Kg/day and 20mg/Kg/day diluted in vehicle) via gavage during lactation (n=9/10). Maternal body weight and chow consumption were assessed during treatment period in the experiment of lactational exposure. In both experiments, the female offspring were evaluated for body weight, body weight gain, and somatic and reflex developmental milestones. Elevated plus maze test was performed on juvenile and adult offspring in both experiments. The following parameters of development and reproductive function were evaluated: anogenital distance, onset of puberty, estrous cycle, weight of genital organs, ovarian and uterine histomorphometry at puberty and adulthood, sexual behavior and fertility testing. Results were compared among groups by parametric two-way ANOVA (for the experiment performed during pregnancy) and one-way ANOVA (for the experiment performed during lactation) tests followed by Tukey's test, and by the non-parametric Kruskal-Wallis test followed by Dunn's test or Chi-square test. Differences were considered statistically significant when p ≤ 0.05. In utero exposure to ST, regardless of exposure to stress, reduced body weight at birth, delayed incisor eruption, increased absolute thyroid weight on postnatal day (PND) 80 and altered the estrous cycle of female rats. Exposure to ST combined with stress also increased the absolute and relative thyroid weight on PND 42, in addition to increasing the relative weight of the thyroids, the absolute weight of uterus and the percentage of ovarian structures on PND 80. In the ST group, reduced body weight on PND 21, reduced body weight gain in the preweaning period, delayed fur development and increased anxiety-related behavior in juvenile offspring were also observed. Treatment with ST during lactation did not change maternal body weight or chow consumption. Lactational exposure to the highest dose of ST reduced body weight on PND 7, while both treated groups had reduced body weight on PND 21. In the group treated with the highest dose of ST, increased relative adrenal gland and pituitary weights were observed on PND 21. The group treated with the dose of 10 mg/kg had a delay in the occurrence of the first estrus and a reduction in the absolute weight of the pituitary gland in the PND 42. Both groups exposed to ST showed a reduction in endometrial height on PND 75 and an increase in relative thyroid weights on PND 42, although only the group treated with the highest dose had increased thyroids on PND 75. In conclusion, the treatment with ST, under these experimental conditions, had repercussions on reproductive parameters, initial growth, thyroid weight, somatic maturation, reflex and neurobehavioral development of female rat offspring, which raises questions regarding the safety of using this antidepressant in human clinical practice during pregnancy and lactation.
The selective serotonin reuptake inhibitors (SSRIs) are the medications of choice for depressive women during gestation e lactation. However, the use of these antidepressants in the pre and postpartum periods has been correlated with several changes in offspring in animals and humans. Sertraline (ST) is one of the most used SSRIs in pregnancy and lactation, but little is known about the impact of its use in these periods, especially in relation to female offspring. Thus, the aim of the present study was to evaluate the effects of gestational (associated or not with stress) and lactational exposure to ST on the somatic, reflex, neurobehavioral and reproductive development of female offspring of Wistar rats. In gestational exposure, pregnant Wistar rats received ST (20 mg/Kg/day diluted in vehicle) by oral gavage associated or not with restraint stress for 1 h/day from gestational days 13 to 20 (n=7-10). In lactational exposure, lactating Wistar rats were treated with ST (10mg/Kg/day and 20mg/Kg/day diluted in vehicle) via gavage during lactation (n=9/10). Maternal body weight and chow consumption were assessed during treatment period in the experiment of lactational exposure. In both experiments, the female offspring were evaluated for body weight, body weight gain, and somatic and reflex developmental milestones. Elevated plus maze test was performed on juvenile and adult offspring in both experiments. The following parameters of development and reproductive function were evaluated: anogenital distance, onset of puberty, estrous cycle, weight of genital organs, ovarian and uterine histomorphometry at puberty and adulthood, sexual behavior and fertility testing. Results were compared among groups by parametric two-way ANOVA (for the experiment performed during pregnancy) and one-way ANOVA (for the experiment performed during lactation) tests followed by Tukey's test, and by the non-parametric Kruskal-Wallis test followed by Dunn's test or Chi-square test. Differences were considered statistically significant when p ≤ 0.05. In utero exposure to ST, regardless of exposure to stress, reduced body weight at birth, delayed incisor eruption, increased absolute thyroid weight on postnatal day (PND) 80 and altered the estrous cycle of female rats. Exposure to ST combined with stress also increased the absolute and relative thyroid weight on PND 42, in addition to increasing the relative weight of the thyroids, the absolute weight of uterus and the percentage of ovarian structures on PND 80. In the ST group, reduced body weight on PND 21, reduced body weight gain in the preweaning period, delayed fur development and increased anxiety-related behavior in juvenile offspring were also observed. Treatment with ST during lactation did not change maternal body weight or chow consumption. Lactational exposure to the highest dose of ST reduced body weight on PND 7, while both treated groups had reduced body weight on PND 21. In the group treated with the highest dose of ST, increased relative adrenal gland and pituitary weights were observed on PND 21. The group treated with the dose of 10 mg/kg had a delay in the occurrence of the first estrus and a reduction in the absolute weight of the pituitary gland in the PND 42. Both groups exposed to ST showed a reduction in endometrial height on PND 75 and an increase in relative thyroid weights on PND 42, although only the group treated with the highest dose had increased thyroids on PND 75. In conclusion, the treatment with ST, under these experimental conditions, had repercussions on reproductive parameters, initial growth, thyroid weight, somatic maturation, reflex and neurobehavioral development of female rat offspring, which raises questions regarding the safety of using this antidepressant in human clinical practice during pregnancy and lactation.
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Palavras-chave
Sertralina, Estresse materno, Gestação, Lactação, Toxicologia reprodutiva