Unraveling sexually dimorphic offspring behaviors: maternal premating stress and the neuro-microbial-metabolic network

Dec 10, 2025Molecular psychiatry

How Mother's Stress Before Pregnancy May Affect Male and Female Offspring Behavior Through Brain, Gut, and Metabolism Links

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Abstract

Premating stress in female mice caused significant neurodevelopmental delays and altered adult behavior in offspring, with sex-dependent differences observed.

Female offspring exhibited hyperactivity and social deficits, while male offspring displayed signs of anxiety.
Cerebellum cytokine levels were reduced in a sex-dependent manner following maternal stress.
Maternal stress altered the gut microbiota composition in offspring, showing distinct microbial taxa associated with each sex.
Male offspring experienced significant metabolic changes and increased agreement between maternal and offspring metabolic profiles.
Lactoferrin intervention improved anxiety in male offspring but did not affect female behavioral deficits.
The study identified a sexually dimorphic network involving gut microbiota, metabolites, and brain profiles linked to intergenerational neuropsychiatric vulnerability.

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Psychosocial stress in women is a major public health concern, yet the intergenerational mechanisms linking maternal premating stress to offspring neuropsychiatric vulnerability remain incompletely understood. Here, female mice were exposed to chronic unpredictable mild stress (CUMS) prior to mating, and offspring were assessed for neurodevelopment, adult behavior, and multi-omics profiles. Premating stress induced neurodevelopmental delays and sexually dimorphic adult phenotypes: female offspring exhibited hyperactivity and social deficits, whereas male offspring displayed anxiety. Cerebellum cytokine levels were reduced in a sex-dependent manner. Maternal stress shifted offspring gut microbiota (GM) composition, with p_Proteobacteria as core taxa in females and p_Firmicutes in males, exhibiting sex-dependent and inverse shifts in microbial network connectivity. Male offspring showed marked metabolic alterations and enhanced maternal-offspring metabolic concordance. Integrated analyses of GM, metabolites, and cerebellum profiles identified sexually dimorphic network correlations, further supported by human data demonstrating maternal stress-induced, sex-dependent GM network remodeling. Lactoferrin (LF) intervention selectively rescued male anxiety but not female behavioral deficits, and in males specifically, reduced cerebellum pro-inflammatory cytokines, enhanced GM network connectivity, and enriched immune-related serum metabolic and cerebellum transcriptomic pathways. LF also suppressed Purkinje cell firing frequency in males and reinforced post-treatment connectivity across microbial, metabolic, and cerebellum transcriptional nodes. Collectively, these findings delineate a previously unrecognized sexually dimorphic neuro-microbiota-metabolic network underpinning intergenerational vulnerability and highlight microbiota-targeted modulation as a systems-level mechanistic framework for sex-specific prevention of maternal stress-associated neuropsychiatric disorders.

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Unraveling sexually dimorphic offspring behaviors: maternal premating stress and the neuro-microbial-metabolic network

Abstract

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