Estrogen Receptor β as a Candidate Regulator of Sex Differences in the Maternal Immune Activation Model of ASD

Abstract

Interestingly, more males are diagnosed with autism spectrum disorder (ASD) than females, yet the mechanism behind this difference is unclear. Genes on the sex chromosomes and differential regulation by sex steroid hormones and their receptors are both candidate mechanisms to explain this sex-dependent phenotype. Nuclear receptors (NRs) are a large family of transcription factors, including sex hormone receptors, that mediate ligand-dependent transcription and may play key roles in sex-specific regulation of immunity and brain development. Infection during pregnancy is known to increase the probability of developing ASD in humans, and a mouse model of maternal immune activation (MIA), which is induced by injecting innate immune stimulants into pregnant wild-type mice, is commonly used to study ASD. Since this model successfully recaptures the behavioral phenotypes and male bias observed in ASD, we will discuss the potential role of sex steroid hormones and their receptors, especially focusing on estrogen receptor (ER)β, in MIA and how this signaling may modulate transcription and subsequent inflammation in myeloid-lineage cells to contribute to the etiology of this neurodevelopmental disorder.

Polymorphism of Estrogen Receptor Genes and Its Interactions With Neurodevelopmental Genes in Attention Deficit Hyperactivity Disorder Among Chinese Han Descent

“…Similarly, there was a trend for ESR1 gene rs6930355 to be associated with ADHD in females but not males. These findings align with previous studies showing that ESR genes affect the sex heterogeneity seen in psychiatric disorders [ 44 - 46 ]. Sexual dimorphism in ADHD has also been reported in our previous studies [ 47 , 48 ].…”

Maternal immune activation as an epidemiological risk factor for neurodevelopmental disorders: Considerations of timing, severity, individual differences, and sex in human and rodent studies

“…For example, estradiol (E2) can inhibit this pathway via increased production of IκBα mRNA ( Xing et al, 2012 ). The expression and activation of ERs vary between males and females, which causes differences in the magnitude and duration of the innate inflammatory response between sexes ( Kovats, 2015 ; Arnold and Saijo, 2021 ). For instance, females have a higher basal expression of ERα and ERβ than males in human blood monocytes-derived macrophages (MDMs) ( Campesi et al, 2017 ).…”

The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior

“…Therefore, studying sex differences in ASD is an interesting issue. In fact, there are more than 80 papers in PubMed on sex influence in different rodent models of ASD (for example, Gouda et al, 2022 ; Ferreira et al, 2022 ; Arnold and Saijo, 2021 ). For this reason, we have performed all our experiments in male, since mixing both sexes surely would arise a high deviation in the data.…”