Chronic Testosterone Administration During Pregnancy Causes Autistic-like Traits in Rat Offspring: Possible Relationships with Cerebral Oxytocin, Dopamine, Serotonin and IGF-1 Levels.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects boys three times more frequently than girls. Previous studies have suggested that higher fetal testosterone exposure can cause autism-like behaviors in males. The mechanism of effect of fetal testosterone on autism development is not well known. In the present study, we investigated the relationship between prenatal testosterone exposure and ASD in an experimental study with the use of behavioral tests, histopathological examinations and biochemical measurements performed to compare offspring with and without exposure to testosterone. Female rats were randomly distributed into Group 1 (control, n = 6) and Group 2 (Testosterone undecanoate, n = 6). Female rats were caged with a fertile male (three female/one male) for 2–3 days during the oestrus period. Group 1 rats were given 1 ml/kg % 0.9 NaCl saline on the 10th day of pregnancy, while Group 2 rats were given 250 mg/kg testosterone undecanoate. The dams were allowed to raise their litters until weaning on postnatal day 21 (P21). On P21 , forty littermates (10 male control, ten female control, ten male Testosterone-exposed, and ten female Testosterone-exposed) were randomly separated and housed. These animals underwent behavioral testing in adulthood on P50. Subsequently, the rats were sacrificed. Biochemical analyses [Brain tissue 5-Hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), Insulin-like growth factor-1 (IGF-1), and oxytocin] and histopathological analyses were performed. Analysis of the behavioral tests (three-chamber social test, open field test) revealed significant differences among the groups, with the testosterone-exposed groups demonstrating autistic traits at a greater degree. Histologically, hippocampal CA1 and CA3 regions displayed significant alterations such as gliosis and neuronal cell death in the testosterone-exposed groups compared to controls. Brain levels of tissue 5-HIAA, HVA, IGF-1 increased while oxytocin level decreased in the testosterone-exposed groups. These results suggest a possible link between chronic prenatal testosterone exposure and neurodevelopmental disorders such as ASD. Testosterone exposure and autism-like traits can be linked to dopamine, serotonin, IGF-1 increase, and oxytocin decrease.