Estresse pré-natal: efeitos em longo prazo no comportamento e no balanço dos metabólitos do triptofano

Abstract

Prenatal stress (PNS) directly interferes with fetal programming, a principle by which the mother's endocrine and metabolic environment can generate long-term consequences in adult offspring. Among the potential neurochemical pathways affected by PNS, the tryptophan metabolism by the kynurenine pathway is still poorly investigated. This study sought to investigate the behavioral and neurochemical consequences of PNS, with an emphasis on monoamines and metabolites of the kynurenine pathway, in the adult offspring of mice exposed to PNS. Pregnant females of Swiss mice were subjected to the restraint stress associated with intense light three times a day during the last week of gestation (days 14-21). The adult offspring of males and females submitted to PNS underwent behavioral tests, including open field, object recognition task, elevated plus maze, social interaction and tail suspension test. For the neurochemical stage, the adult offspring were euthanized and their brains dissected in order to quantify the levels of tryptophan, quinolinic acid (QA), kynurenine, 5- hydroxyindole acetic acid (5-HIAA), serotonin (5-HT), dopamine and noradrenaline in the hippocampus and brainstem, using the mass spectrometry technique. The prefrontal cortex (PFC) and hippocampus of the offspring were also dissected in order to evaluate the gene expression of the following enzymes: indoleamine 2,3-dioxigenase (IDO), kynurenine monoxygenase (KMO) and kynurenine -aminotransferase 3 (KYAT3), through the real-time PCR technique. The results revealed that the adult offspring submitted to the PNS presented: (1) impairment in the object recognition task in the male and female offspring, with the latter being associated with the estrous cycle; (2) hyperactivity of the male offspring, accessed by the greater total distance travelled in the open field, as well as longer time spent in the closed arms in the elevated plus maze test, suggesting an anxious phenotype, with no changes in monoamine levels, but with changes in metabolites of the quinurenine pathway, defined by higher levels of QA in the hippocampus and brainstem and higher levels of kynurenine and tryptophan exclusively in the hippocampus, (3) increased immobility in the tail suspension test by the female offspring, suggesting a depressive profile, influenced by the phases of the estrous cycle, and associated with lower levels of 5-HT in the hippocampus and greater activity of 5-HT in the hippocampus and brain stem, (4) alteration in the gene expression of enzymes related to the kynurenine pathway, so that PNS females had higher expression of KYAT3 in the hippocampus and IDO in the PFC, while the male offspring showed reduced levels of KMO in the PFC. In conclusion, this study revealed a sex dependent behavioral and neurochemical profile as a consequence of late PNS in the mice offspring, evaluating the balance of tryptophan metabolites as a key point.