Table 1. Potential contributing mechanisms underlying the sex-biased prevalence of ASD as demonstrated in preclinical rodent models

Potential contributing mechanisms	Preclinical models showing sexually dimorphic ASD-like phenotypes	Suggested mechanism(s)	References
Synaptic dysfunction	Shank3 KO	Reduced levels of mGluR5 in male mice	[27]
	Chd8+/N2373K	Sexually dimorphic changes in neuronal activity, synaptic transmission, and transcriptomic profiles	[40]
	Fmr1 KO	Sexually dimorphic upregulation of ASD risk genes(male↑: Ctnnb1a and Grin1a, female↑: Homer1a, Ptgs2a, Drd1a, Pik3cab, and Csnk1g1b)	[44]
Microglial abnormalities	Cntnap2 KO	Activated morphology and phagocytosis of synaptic structures in male microglia	[58]
	DEP/MS	Hyper-ramified phenotype in male microglia	[63]
Hormones	VPA-induced ASD mouse model	Lower levels of TH expression in the AVPV of male mice	[70]
	Placenta-specific Akr1c14 KO	Male mouse-specific abnormalities in cerebellar white matter	[75]
Escape from X chromosome inactivation	Prenatal stress model	Placental OGT expression levels are twice as high for female fetuses as for male fetuses; this results in sexually distinct gene expression in trophoblasts through epigenetic modulation by histone methylation	[79,80]
Integrated stress response pathway	MIA (Poly[I:C])	Hyperactivation of the ISR pathway in male MIA offspring, resulting in reduced nascent protein synthesis in the brain	[85]
Immune pathways	Prenatal GBS infection	Heightened levels of pro-inflammatory cytokines and chemokines such as IL-1β and CINC-1/CXCL1 in male fetuses	[98]
	MIA (LPS)	Male MIA offspring exhibit heightened cortical hypoxia, reduced mitosis of radial glial cells, disrupted E/I balance within the brain, severe placental necrosis, elevated inflammation, and reduced placental growth	[99]
	MIA (two-hit model)	The anti-inflammatory cytokines IL-10 and TGF-β1 are decreased in male offspring but increased in female mice	[100]

upregulated,
high-confidence risk genes for ASD,
suggestive risk genes for ASD.
ASD, autism spectrum disorder; Shank3, SH3 and multiple ankyrin repeat domains 3; KO, knockout; mGluR5, metabotropic glutamate receptor 5; Chd8, chromodomain helicase DNA-binding protein 8; Fmr1, fragile X mental retardation 1; Ctnnb1, catenin beta 1; Grin1, glutamate ionotropic receptor NMDA type subunit 1; Homer1, homer scaffold protein 1; Ptgs2, prostaglandin-endoperoxide synthase 2; Drd1, dopamine receptor D1; Pik3ca, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; Csnk1g1, casein kinase 1 gamma 1; Cntnap2, contactin-associated protein 2; DEP/MS, diesel exhaust particles and maternal stress; VPA, valproic acid; TH, tyrosine hydroxylase; AVPV, anteroventral periventricular nucleus; Akr1c14, aldo-keto reductase family 1 member C4; OGT, O-linked-N-acetylglucosamine transferase; MIA, maternal immune activation; poly(I:C), polyinosinic:polycytidylic acid; ISR, integrated stress response; GBS, Group B Streptococcus; IL-1β, interleukin 1 beta; CINC-1/CXCL1, cytokine-induced neutrophil chemoattractant-1; LPS, lipopolysaccharide; E/I, excitation/inhibition; IL-10, interleukin 10; TGF-β1, transforming growth factor beta 1.