Desenvolvimento embrionário em ratas tratadas com tacrolimus durante a fase de pré-implantação

Abstract

ObjetivO: avaliar a toxicidade do tacrolimus sobre o desenvolvimento embrionário em ratas tratadas durante o período de trânsito tubário. MétOdOs: sessenta ratas Wistar foram distribuídas em quatro grupos (15 animais cada), que receberam diferentes doses de tacrolimus por via intragástrica: (T1) 1,0 mg/kg/dia, (T2) 2,0 mg/kg/dia e (T3) 4,0 mg/kg/dia. O grupo controle (C) recebeu água destilada. As ratas foram observadas diariamente para detectar sinais clínicos de toxicidade. O tratamento foi realizado do primeiro ao quinto dia de gestação. As seguintes variáveis maternas foram analisadas: peso corporal, de ovários, fígados e rins, consumo de alimento, número de corpos lúteos, implantes, fetos vivos e mortos e índice de implantação. Os fetos e placentas foram pesados e os primeiros foram observados para detectar malformações externas. Estatística: análise de variância (ANOVA), uma via, seguida de teste de Dunnett (alfa=0,05). ResultadOs: não ocorreram indícios clínicos de toxicidade materna, tais como perda de peso, redução do consumo de alimento ou do peso de órgãos (p>0,05). Também não houve diferença significativa no peso corporal dos fetos (C: 1,8±0,6; T1: 2,2±0,5; T2: 1,9±0,5 e T3: 2,0±0,5 g) e de placentas (C: 1,6±0,4; T1: 1,5±0,4; T2: 1,8±0,4 e T3: 1,6±0,4 g), com p>0,05. Nenhuma malformação externa foi detectada. COnClusões: a administração de tacrolimus a ratas prenhes durante o período de trânsito tubário não parece ter qualquer efeito tóxico e materno ou embrionário. AbstractPuRPOse: to evaluate the toxicity of tacrolimus on embryonic development in rats treated during the tubal transit period. MethOds: sixty Wistar rats were distributed into four groups (15 animals each), which received different doses of tacrolimus through intragastric administration: (T1) 1.0 mg/kg/day, (T2) 2.0 mg/kg/day and (T3) 4.0 mg/kg/day. The control group (C) received distilled water. The rats were observed daily to detect clinical signs of toxicity. The treatments were performed from the first to the fifth day of pregnancy. The following maternal variables were analyzed: body, ovary, liver, and kidney weights, food intake, number of corpora lutea, implants, alive and dead fetuses, and implantation rates. The fetuses and placentae were weighed and the former were observed in order to detect external malformation. Statistical analysis was performed by one way: analysis of variance (ANOVA), folowed by the Dunnet test (alpha=0.05). Results: there were no signs of maternal toxicity, such as body weight loss, decrease in food intake or in organ weights (p>0.05).

Teratogenic Effect of Usnic Acid from Cladonia substellata Vainio during Organogenesis

“…Signs of maternal toxicity may be related to the reduction of body weight, followed or not by a decrease in food consumption; changes in weight and/or morphology of the bodies; and the occurrence of deaths during the treatment period. Our results showed that administration of usnic acid in both doses tested interfered in maternal weight gain during pregnancy, signaling an indication of maternal toxicity of the compound [35]. …”

Tacrolimus and Sirolimus Induce Reproductive Abnormalities in Female Rats

“…SIR has been associated with reversible gonadal dysfunction and infertility in a small cohort of men and women after kidney transplant (15). Animal studies have shown that TAC given to pregnant Wistar rats does not have any toxic effect on mother/embryo (16). The PCOS phenotype is characterized by anovulatory cycles, hyperandrogenism, and infertility and is associated with insulin resistance (17).…”

Tacrolimus in the prevention of adverse pregnancy outcomes and diabetes-associated embryopathies in obese and diabetic mice

“…On the other hand, Farley and co-workers [ 31 ] recounted normal maternal health but dose-dependant elevation in the percentages of post-implantation resorption that led to the conclusion of a relative safety to the use of tacrolimus in pregnancy [ 31 ]. Similarly, Ramos et al [ 36 ] reported on normal maternal and fetal health in otherwise normoglycemic female Wistar rats orally receiving tacrolimus at 10–40 times the currently described dosage. Notwithstanding species and route of administration related-differences in interpreting tacrolimus pharmacokinetics among mice, rats and women, our data are generally supportive of previous reports from clinical registry leveraging records from 20 to 200 women receiving 0.1–0.4 mg/kg/day tacrolimus mono-therapy or in a combination of immunosuppression whereby higher fetal exposure ratios were found to be exponentially related to higher maternal trough blood concentrations of the compound but reported on normal birth weights and post-natal development in these pregnancies [ 28 , 35 , 37 – 39 ].…”

“…This is an important consideration because tacrolimus, like most drugs, crosses the placenta with concentrations found in the cord blood being ~71, 23 and 19% of maternal concentrations for whole blood, plasma and unbound form, respectively [ 28 , 39 ]. Even with transfer across the placenta, tacrolimus neither causes gross congenital malformations in humans [ 10 , 32 , 40 , 41 ] nor does it in normoglycemic Wistar rats exposed for 15 days to about 10–40× the current dose per oral during peri-implantation phase [ 36 ]. Nevertheless, tacrolimus has been reported to cause transient and reversible materno-fetal comorbidities such as hyperkalemia and in some cases reduced renal mass (oligonephronia) thereby increasing the risk for further development of renal failure and hypertension in adult life [ 40 , 42 ].…”