OBJECTIVE: To investigate the molecular mechanisms of the adverse effects of exposure to sulfamonomethoxin (SMM) in pregnancy on the neurobehavioral development of male offspring. METHODS: Pregnant mice were randomly divided into four groups: control- (normal saline), low- [10 mg/(kg•day)], middle- [50 mg/(kg•day)], and high-dose [200 mg/(kg•day)] groups, which received SMM by gavage daily during gestational days 1-18. We measured the levels of short-chain fatty acids (SCFAs) in feces from dams and male pups. Furthermore, we analyzed the mRNA and protein levels of genes involved in the mammalian target of rapamycin (mTOR) pathway in the hippocampus of male pups by RT-PCR or Western blotting. RESULTS: Fecal SCFA concentrations were significantly decreased in dams. Moreover, the production of individual fecal SCFAs was unbalanced, with a tendency for an increased level of total fecal SCFAs in male pups on postnatal day (PND) 22 and 56. Furthermore, the phosphatidylinositol 3-kinase (PI3k)/protein kinase B (AKT)/mTOR or mTOR/ribosomal protein S6 kinase 1 (S6K1)/4EBP1 signaling pathway was continuously upregulated until PND 56 in male offspring. In addition, the expression of Sepiapterin Reductase (SPR), a potential target of mTOR, was inhibited. CONCLUSION In utero exposure to SMM, persistent upregulation of the hippocampal mTOR pathway related to dysfunction of the gut (SCFA)-brain axis may contribute to cognitive deficits in male offspring.
Alcohol Oxidoreductases ; metabolism ; Animals ; Anti-Infective Agents ; toxicity ; Fatty Acids, Volatile ; analysis ; Feces ; chemistry ; Female ; Hippocampus ; drug effects ; metabolism ; Male ; Memory ; drug effects ; Mice, Inbred ICR ; Pregnancy ; Prenatal Exposure Delayed Effects ; Sulfamonomethoxine ; toxicity ; TOR Serine-Threonine Kinases ; metabolism