Paternal infections and immune activation program offspring neurobehavior in a sex-dependent manner.

Preconception immune challenges in fathers are increasingly recognized as biologically meaningful determinants of offspring neurodevelopment, behavior, and immunity. However, the field still lacks a unifying framework to explain the recurrent sex dependence of these inherited outcomes. Here, we synthesize evidence across paternal infection and immune activation paradigms, including SARS-CoV-2 infection, parasitic infection, fungal infection, polymicrobial sepsis, and pathogen mimic-induced models of immune activation. We treat offspring sex as a central organizing variable rather than a secondary feature. Across models, inherited effects may be male biased, female biased, or shared but expressed in different physiological domains, arguing against a single narrative of male vulnerability or female resilience. Causal sperm RNA studies after paternal viral and parasitic infection support a transmission-versus-decoding framework in which germline signals can be shared while developmental interpretation diverges between male and female offspring. Evidence from paternal stress, metabolic disturbance, and toxicant exposure reveals related patterns of sperm epigenetic remodeling and sex-biased offspring outcomes, suggesting that similar transmission and developmental decoding mechanisms may operate across diverse paternal exposures. We further integrate evidence that paternal immune challenges differ in immune polarity, producing offspring immune priming in some models and tolerization in others, often with sex-dependent strength and direction. Finally, we discuss candidate mechanisms of sex-specific decoding, including placental dimorphism, hormone-immune interactions, and sex chromosome biology, and outline priorities for future studies combining longitudinal sperm profiling with sex-stratified embryonic, placental, behavioral, and immune phenotyping.