Exposición prenatal a contaminantes ambientalesexposición prenatal a clorpirifós y el desarrollo de autismo

Abstract

Organophosphate pesticides are a group of chemical compounds that have been used in very different areas, such as residential use, the care of public gardens, and, above all, in agricultural fields as a pesticide. Within this type of compound, chlorpyrifos has been one of the most used, and, like the rest of the substances belonging to this family, it is considered a dangerous neurotoxin. Its main mechanism of action is the irreversible inhibition of acetylcholinesterase (AChE), although also, over the last few years, it has been possible to verify how even with subtoxic doses (those that do not produce the irreversible inhibition of AChE) there is an increase in oxidative stress, loss of neurons in certain brain structures, and neuroinflammation, among others. These kinds of alterations have been related to numerous psychiatric conditions, among which we can highlight the Autism Spectrum Disorder. In fact, the incidence of autism is higher in people who, for vital reasons, such as living near a farm field, have been exposed to this type of substance during their development. On the other hand, it is known that exposure to valproic acid during fetal development causes autism. In fact, it is one of the most widely used animal models, as it covers a wide range of very similar aspects, both at a behavioral level (low social interaction, impulsive control disorders, or repetitive patterns of behavior); as well as at the physiological level (teratogenicity, alteration of the excitatoryinhibitory balances of the brain, etc). In order to make a comparison between the effects of prenatal exposure of both compounds, we have administered subtoxic doses of chlorpyrifos of 1 mg/kg to Wistar rats, between gestational days (GD) 12.5-15.5, and a dose of valproic acid of 400 mg/kg, on 12.5 (GD). The results obtained in the ultrasound tests, carried out between postnatal days (PND) 7 and 8, have highlighted an important similarity between both groups, chlorpyrifos (CPF) and valproic acid (VPA), compared to the control group (CNT). Both CPF and VPA took longer to make their first call, as well as fewer calls throughout the test. This indicates that they express less motivation to warn the mother of their adverse situation. In the locomotion tests, we have observed how the CPF is more active during adolescence compared to the CNT, something that does not occur in adulthood. Furthermore, no significant differences in CPF have been observed in the drug-challenge. In the 3-room test, in which both sociability and reaction to social novelty are evaluated, both those exposed to CPF and VPA were similar to each other compared to the CNT. More specifically, the CPF, in their adolescence, showed a negative index in the reaction to social novelty, closely followed by those exposed to VPA. An effect that was recovered in adulthood, showing that CPF is more social even than the controls. The metabolomic analyzes, in line with what was seen in the behavioral tests, also showed that there are similarities between those exposed to CPF and those exposed to VPA in adolescence, being in adulthood where they showed a more pronounced difference in the amount of GABA, more specifically, in the cerebellum. Thus, however, it seems that, indeed, although far from representing a model of autism, prenatal exposure to subtoxic doses of CPF can give rise to alterations very similar to those seen in an accepted autistic animal model, such as VPA. As well as that these alterations caused by CPF are more prone to recovery during the ontogeny of the animal than those caused by VPA.