Considering the increased risk of cognitive deficits and mood disorders programming associated with bisphenol exposure, we used a preclinical model to identify short- and long-term effects of early exposure to Bisphenol A (BPA) and its replacement, Bisphenol S (BPS), on the central cholinergic and serotonergic systems. Wistar female and male rats born to dams exposed to BPA or BPS (both at 10 μg/kg/day or 50 μg/kg/day) during pregnancy and lactation were euthanized at weaning or adulthood. Cholinergic and serotonergic biomarkers were assessed in the frontal cortex and pons + medulla oblongata. BPA and BPS disrupted these systems, with outcomes depending on the specific bisphenol, biomarker, and time point. Effects also varied across brain regions and between sexes. The nicotinic cholinergic receptor showed more pronounced alterations than the presynaptic choline transporter. Both serotonergic receptors—5-HT1AR and 5-HT2R—were affected; however, the serotonergic transporter remained unchanged. Increased binding was the predominant effect for both systems. Maternal exposure to BPA, even at low doses, induces sex-dependent short- and long-term changes in the cholinergic and serotonergic systems of the progeny. BPS affects these same neurotransmitter systems, although leading to compound-specific outcomes. These results pose both BPA and BPS as neurotoxicants that compromise neurodevelopment and program disorders later in life.

Background/Objectives: Schizophrenia and nicotine misuse are a comorbid condition that frequently develops during adolescence. Considering the role of the nucleus accumbens (NAcc) as a common neurobiological substrate for these psychiatric disorders, label-free proteomics was employed to identify NAcc deregulated proteins in male and female mouse models of schizophrenia with a history of adolescent nicotine exposure. Methods: Phencyclidine was used to model schizophrenia, and minipump infusions were used to model nicotine misuse. Results: Enrichment Reactome pathway and protein–protein interaction analyses showed that the cytoskeleton and associated synaptic plasticity mechanisms, energy metabolism, and nervous system development were affected in both sexes. In particular, Ncam1 (Neural cell adhesion molecule 1) could be of interest as a candidate marker of synaptic plasticity disbalance. Its deregulation in the NAcc of both sexes suggests that it lies at the core of the comorbidity pathophysiology. When considering sex-selective effects, Cs (Citrate synthase) and Mapk3 (Mitogen-activated protein kinase 3) were identified as exclusively deregulated in female and male mice, respectively. Since both proteins were previously shown to be exclusively deregulated in the medial prefrontal cortex of co-modeled mice, a common mesocortical and mesolimbic system effect can be inferred, supporting the role of aberrant energy metabolism and synaptic plasticity in the comorbidity model. Conclusions: The current data provide insights into the NAcc proteome disbalance in an adolescent preclinical model of combined schizophrenia and nicotine misuse, pointing to relevant pathways and early markers of the comorbidity.

Schizophrenia and nicotine misuse comorbidity frequently emerges during adolescence. Although the dorsal striatum has received less attention than mesolimbic regions in this context, growing evidence supports its involvement in both schizophrenia-related dysfunction and the transition to compulsive drug-seeking. Here, we investigated dorsal striatal proteomic alterations in adolescent male and female C57BL/6 mice modeled to schizophrenia (phencyclidine: 2.5 mg/kg, s.c., 15 days) with a history of nicotine exposure (nicotine: 24 mg/kg/day, minipump infusions, 7 days). Dorsal striatum samples were analyzed by label-free quantitative proteomics, followed by Reactome pathway enrichment and interactome map analyses. Co-exposure induced sex-dependent alterations. Females exhibited greater proteomic disruption, whereas in males, co-exposure amplified phencyclidine-associated alterations while attenuating nicotine-driven effects. Across sexes, convergent enrichment was observed in pathways related to immune signaling, metabolic regulation and signal transduction. Female interactome analysis identified glyceraldehyde-3-phosphate dehydrogenase (Gapdh) as the most highly connected node linked to proteins involved in bioenergetics, RNA processing, and apoptosis, while the male network was centered on peptidyl-prolyl cis-trans isomerase (Fkbp1a) and associated with proteostasis-related processes. Our results identify the dorsal striatum as an emerging molecular target in an animal model combining schizophrenia-related and nicotine exposure-related insults and highlight pathways and candidate molecular markers to be further investigated and validated.