Influência da exposição in utero e lactacional ao anti-inflamatório ibuprofeno: repercussão tardia em parâmetros reprodutivos masculinos, em ratos
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Data
2018-02-20
Autores
Balin, Paola da Silva
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Universidade Estadual Paulista (Unesp)
Resumo
Os anti-inflamatórios não esteroidais (AINEs), entre eles o Ibuprofeno, são amplamente utilizados para o tratamento da dor e de processos inflamatórios, e estão entre as classes de medicamentos mais utilizadas por gestantes. Através da inibição da enzima ciclo-oxigenase, os AINEs inibem a síntese de prostaglandinas, compostos eicosanoides que atuam não somente como mediadores e moduladores inflamatórios, mas também em diversos processos fisiológicos do organismo, como no mecanismo de diferenciação sexual hipotalâmica. O processo de masculinização do hipotálamo é dependente de testosterona, que por ação da enzima citocromo P450 aromatase, é convertida em estradiol. Este hormônio regula positivamente a expressão da enzima ciclo-oxigenase no hipotálamo, aumentando a produção de prostaglandina do subtipo E2 (PGE2), que atua aumentando a formação de espinhas dendríticas no núcleo sexualmente dimórfico da área pré-optica (SDN-POA). Em virtude da importância da PGE2 no processo de diferenciação sexual hipotalâmica, torna-se preocupante o uso de anti-inflamatórios durante a gestação. Desta forma, o objetivo desse estudo foi avaliar os possíveis efeitos resultantes da exposição in utero e lactacional ao ibuprofeno e suas repercussões tardias sobre parâmetros reprodutivos masculinos em ratos machos. Para tanto, ratas prenhes foram expostas a três doses de ibuprofeno (10; 30; 60 mg/kg) entre a última semana de prenhez (Dias gestacionais 15-21) até o final da lactação (Dias pós-natal 21) por gavage. Durante o tratamento, foram monitorados o consumo de água e ração, massa corporal e comportamento materno das ratas expostas. Após o desmame, coletou-se o sangue das mães para análises bioquímicas e órgãos para registro do peso. Após o nascimento, os filhotes machos foram avaliados através dos seguintes parâmetros: massa corporal, distância anogenital e idades de descida testicular e separação prepucial. Na vida adulta, estes mesmos animais foram investigados em relação a parâmetros comportamentais (comportamento sexual masculino e feminino e preferência sexual), fertilidade, parâmetros espermáticos (contagem, motilidade e morfologia espermática), pesos de órgãos reprodutores, dosagem hormonal, quantificação do volume do SDN-POA e histologia de testículo e epidídimo. O tratamento com ibuprofeno não alterou os parâmetros maternos avaliados. A prole masculina apresentou redução na massa corporal e na distância anogenital, bem como, atraso nas idades de descida testicular e separação prepucial. Na vida adulta, os animais apresentaram redução nos níveis séricos de testosterona e no volume do núcleo de célula de Leydig. A exposição ao ibuprofeno não alterou os pesos dos órgãos reprodutores, a contagem espermática, a fertilidade ou o número de células de Sertoli, entretanto causou diminuição no número de espermatozoides normais. Em relação aos parâmetros comportamentais, os animais expostos ao ibuprofeno apresentaram tanto comportamento sexual masculino quanto feminino, contudo não houve alteração em relação ao padrão de preferência sexual. O volume total do SDN-POA não foi alterado. Concluiu-se que o ibuprofeno, nestas condições experimentais, foi capaz de perturbar a programação do eixo hipotálamo-hipófise-gônada, afetou a maturação sexual e as funções reprodutivas masculinas.
Non-steroidal anti-inflammatory drugs (NSAID), including Ibuprofen, are widely used in the treatment of pain and inflammatory processes, and are of the most commonly classes of drugs used by pregnant women. By inhibiting the cyclooxygenase enzyme (COX), NSAID inhibit the synthesis of prostaglandins, eicosanoids compounds that act not only as mediators and inflammatory modulators, but also in various physiological processes of the organism, such as in the mechanism of sexual hypothalamic differentiation. The hypothalamus masculinization process is testosterone dependent, which by action of the aromatase cytochrome P450 enzyme is metabolized to estradiol. This hormone upregulates the expression of COX enzyme in the hypothalamus, increasing the production of prostaglandin E2, which acts by increasing the formation of dendritic spines in the neurons of the sexually dimorphic nucleus of the preoptic area in males (SDN-POA). Due to the importance of prostaglandin E2 in the process of hypothalamic sexual differentiation, the use of anti-inflammatory drugs during pregnancy is of concern. Thus, the aim of this study was to evaluate the possible effects resulting from in utero and lactation exposure to non-steroidal anti-inflammatory ibuprofen and its late repercussions on male reproductive parameters in male rats. For this, pregnant rats were exposed to three doses of ibuprofen (10; 30; 60 mg/kg) between the last week of pregnancy (Gestational Days 15-21) until the end of lactation (Postnatal Days 21) by gavage. During treatment, water consumption, food intake, body weight and maternal behavior of the dams were monitored. After weaning, blood samples was collected for biochemical analyzes and organs for weight recording. After birth, male offspring were evaluated through the following parameters: body weight, anogenital distance and ages of testicular descent and preputial separation. In the adult life, these same animals were investigated in relation to behavioral parameters (male and female sexual behavior and sexual preference), fertility, sperm parameters (sperm count, sperm motility and sperm morphology), reproductive organ weights, hormonal levels, volume of the SDN-POA and histology of testis and epididymis. Treatment did not affect any of the maternal parameters evaluated. Male offspring presented reduction in body weight and anogenital distance, as well as delay in the ages of testicular descent and preputial separation. In adulthood, these animals showed reduced serum testosterone levels and the volume of Leydig cell nucleus. Exposure to ibuprofen did not alter reproductive organ weights, sperm count, fertility or the number of Sertoli cells; however it resulted in a decrease in the number of normal sperm. Regarding the behavioral parameters, the animals exposed to ibuprofen presented both male and female sexual behavior, but there was no change in relation to the pattern of sexual preference. The total volume of the sexually dimorphic nucleus of the preoptic area was not altered. It was concluded that ibuprofen, under these experimental conditions, was able to disturb the hypothalamic-pituitary-gonadal axis programming, affected sexual maturation and male reproductive functions.
Non-steroidal anti-inflammatory drugs (NSAID), including Ibuprofen, are widely used in the treatment of pain and inflammatory processes, and are of the most commonly classes of drugs used by pregnant women. By inhibiting the cyclooxygenase enzyme (COX), NSAID inhibit the synthesis of prostaglandins, eicosanoids compounds that act not only as mediators and inflammatory modulators, but also in various physiological processes of the organism, such as in the mechanism of sexual hypothalamic differentiation. The hypothalamus masculinization process is testosterone dependent, which by action of the aromatase cytochrome P450 enzyme is metabolized to estradiol. This hormone upregulates the expression of COX enzyme in the hypothalamus, increasing the production of prostaglandin E2, which acts by increasing the formation of dendritic spines in the neurons of the sexually dimorphic nucleus of the preoptic area in males (SDN-POA). Due to the importance of prostaglandin E2 in the process of hypothalamic sexual differentiation, the use of anti-inflammatory drugs during pregnancy is of concern. Thus, the aim of this study was to evaluate the possible effects resulting from in utero and lactation exposure to non-steroidal anti-inflammatory ibuprofen and its late repercussions on male reproductive parameters in male rats. For this, pregnant rats were exposed to three doses of ibuprofen (10; 30; 60 mg/kg) between the last week of pregnancy (Gestational Days 15-21) until the end of lactation (Postnatal Days 21) by gavage. During treatment, water consumption, food intake, body weight and maternal behavior of the dams were monitored. After weaning, blood samples was collected for biochemical analyzes and organs for weight recording. After birth, male offspring were evaluated through the following parameters: body weight, anogenital distance and ages of testicular descent and preputial separation. In the adult life, these same animals were investigated in relation to behavioral parameters (male and female sexual behavior and sexual preference), fertility, sperm parameters (sperm count, sperm motility and sperm morphology), reproductive organ weights, hormonal levels, volume of the SDN-POA and histology of testis and epididymis. Treatment did not affect any of the maternal parameters evaluated. Male offspring presented reduction in body weight and anogenital distance, as well as delay in the ages of testicular descent and preputial separation. In adulthood, these animals showed reduced serum testosterone levels and the volume of Leydig cell nucleus. Exposure to ibuprofen did not alter reproductive organ weights, sperm count, fertility or the number of Sertoli cells; however it resulted in a decrease in the number of normal sperm. Regarding the behavioral parameters, the animals exposed to ibuprofen presented both male and female sexual behavior, but there was no change in relation to the pattern of sexual preference. The total volume of the sexually dimorphic nucleus of the preoptic area was not altered. It was concluded that ibuprofen, under these experimental conditions, was able to disturb the hypothalamic-pituitary-gonadal axis programming, affected sexual maturation and male reproductive functions.
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Palavras-chave
Prostaglandinas, diferenciação sexual hipotalâmica, área pré-óptica, núcleo sexualmente dimórfico, comportamento sexual, Prostaglandins, hypothalamic sexual differentiation, preoptic area, sexually dimorphic nucleus, sexual behavior