Gestational hypothyroxinemia causes autistic-like behaviors, increases proinflammatory traits, and alters glutamatergic protein expression in mouse adult offspring of both sexes.

Abstract

Prevalence of autism spectrum disorder (ASD) has increased over the past three decades. In this regard, there is growing evidence suggesting that environmental factors during pregnancy may contribute as risk factors for ASD, potentially playing a role in this rising trend. Gestational hypothyroxinemia (HTX) is an asymptomatic and frequent thyroid condition characterized by low levels of thyroxine (T4) in blood, with normal range of T3 and TSH. When this condition occurs in early pregnancy it impairs fetal neurodevelopment and diminishes cognitive capacities in the offspring. Additionally, retrospective human studies have shown that gestational HTX is associated with autistic outcomes in the offspring, however, there is an absence of knowledge about the cellular and molecular autism-like traits in the offspring gestated under gestational HTX (HTX-offspring). In this work, autistic-like phenotypes were evaluated in HTX-offspring, using a mouse model of gestational HTX. Consistent with autism-like behaviors of mice models, HTX-offspring exhibited anxiety-related behavior and impaired social interaction skills. Similar to humans, these features were more pronounced in male HTXoffspring. At the molecular level, the expression of NLGN3 and HOMER1 was increased in the prefrontal cortex and hippocampus of male HTX-offspring, compared to the offspring gestated under euthyroidism. Moreover, HTX-offspring showed increased proinflammatory cytokines in serum and an increased ratio of Th17 lymphocytes relative to T regulatory lymphocytes (Th17/Treg), as well as high neuroinflammatory-like traits in the prefrontal cortex and hippocampus, which were also more pronounced in male HTX-offspring. Notably, by administering T4 to pregnant mice during the induction of HTX, the offspring was protected from developing the observed autism-like traits. These findings support that gestational HTX constitutes a significant risk factor for the development of autism-like phenotypes in the offspring and strongly emphasizes the importance of monitoring thyroid function in early pregnancy.