Maternal lead exposure induces sex-dependent cerebellar glial alterations and repetitive behaviors

Abstract

Lead (Pb) is one of the most prevalent heavy metals we encounter daily. Although there are many reports regarding their toxic effects on humans, the effects of exposure to low lead concentrations throughout the pregnancy period on the offspring are not fully elucidated yet. This study aimed to investigate the cellular mechanisms that occur in response to lead exposure. To this end, we administered lead-containing water to pregnant mice from the day of conception till delivery or till day 28 postnatally. Furthermore, we performed neurodevelopmental disorder-related behavior tests and RNA-sequencing analysis. We used both genders for all experiments because neurodevelopmental disorders usually show several sex-dependent differences. The results revealed increased levels of gliosis in the cerebella of lead-exposed pups compared to those in littermates belonging to the control group. Additionally, we observed altered behaviors of male mice in the autism spectrum disorder-related tests. RNA-sequencing results revealed changes in gamma-aminobutyric acid (GABA) signaling in the lead-exposed mouse model. Specifically, the lead-exposed male mice showed decreased monoamine oxidase B and increased levels of diamine oxidase enzyme, which is related to the synthesis of GABA in astrocytes. These findings demonstrate sex-dependent basal developmental changes in glial cells and an increased prevalence of autistic-like behaviors in the young pups of mothers exposed to lead during pregnancy.

Necessity of an Integrative Animal Model for a Comprehensive Study of Attention-Deficit/Hyperactivity Disorder

“…According to a recent report, only male mice show repetitive behavioral and glial changes in their offspring after exposure to low lead concentrations during pregnancy. The expression patterns of glia-related molecules vary according to gender differences [72]. Therefore, it is necessary to include both males and females in ADHD animal models.…”

Microglia and astrocytes underlie neuroinflammation and synaptic susceptibility in autism spectrum disorder

“…For example, high expression levels of microglia markers were observed in males ( Werling et al, 2016 ). In a model of exposure to low lead concentrations during pregnancy, increased glial cells proliferation in the cerebellum of lead-exposed male pups led to an increased incidence of autism-like behavior, suggesting that sex-dependent glial cells influence the incidence of autism-like behavior ( Choi et al, 2022 ). Further evidence regarding sex-specific differences in microglia could be found.…”

“…Previous studies have reported reductions in GABAergic interneurons and transmission in mouse models of ASD ( Kim et al, 2020 ). Furthermore, in a model of maternal lead exposure, astrogliosis was able to prevent behavioral changes by ensuring high GABA levels ( Choi et al, 2022 ). Meanwhile, inhibition of abnormally elevated GABAergic synaptic transmission in the hippocampal CA1 region has been shown to restore E/I balance and rescue autism-like behavior ( Chen et al, 2022 ).…”