Developmental manganese, but not concurrent lead exposure, alters social processing selectively in male mice

Exposure to environmental pollutants, including heavy metals, during fetal life and early childhood, represents a major public health concern. While the health effects of exposure to a single metal have been well documented, real-life scenarios including simultaneous exposure to multiple metals have not yet been extensively investigated. In this study, we investigated the neurobehavioral effects and hippocampal transcriptomic alterations in mouse offspring developmentally exposed to lead (Pb), manganese (Mn), or their combination. Female mice were exposed to environmentally relevant low doses of Pb (100 ppm), Mn (2g/L), or both, via drinking water beginning two weeks prior to conception and continuing throughout gestation and lactation. Offspring of both sexes were assessed at multiple developmental stages using a comprehensive behavioral test battery to identify age- and sex-specific effects of exposure. For transcriptomic analysis, one male and one female (two month-old) from six litters per group (naive siblings of behaviorally tested mice) were euthanized for hippocampal tissue collection. Our novel finding was a specific deficit in social recognition in adult males developmentally exposed to Mn, an effect not observed in the Pb+Mn co-exposure group. To explore potential molecular mechanisms underlying the Mn-associated behavioral phenotype in males, we focused on differentially expressed genes (DEGs) with |logFC| > 1.5 and p < 0.01. Among these, Mup3 (major urinary protein 3) emerged as particularly notable due to its role in pheromonal communication and its potential link to the altered social investigation behaviors observed in Mn-exposed males. Overall, our behavioral data suggest that developmental exposure to Pb or Mn alone, but not in combination, elicits adverse neurobehavioral outcomes, particularly in males. Importantly, the pronounced effects of individual metal exposure, along with the apparent antagonistic interaction in the combined exposure group, were mirrored at the transcriptomic level.