Mice exposed to bisphenol A exhibit depressive-like behavior with neurotransmitter and neuroactive steroid dysfunction

Abstract

Fetal exposure to endocrine disrupting chemicals (EDCs) has been associated with adverse neurobehavioral outcomes across the lifespan and can persist across multiple generations of offspring. However, the underlying mechanisms driving these changes are not well understood. We investigated the molecular perturbations associated with EDC-induced behavioral changes in first (F1) and second (F2) filial generations, using the model EDC bisphenol A (BPA). C57BL/6J dams were exposed to BPA from preconception until lactation through the diet at doses (10 μg/kg bw/d-lower dose or 10 mg/kg bw/d-upper dose) representative of human exposure levels. As adults, F1 male offspring exhibited increased depressive-like behavior, measured by the forced swim test, while females were unaffected. These behavioral changes were limited to the F1 generation and were not associated with altered maternal care. Transcriptome analysis by RNA-sequencing in F1 control and upper dose BPA-exposed adult male hippocampus revealed neurotransmitter systems as major pathways disrupted by developmental BPA exposure. High performance liquid chromatography demonstrated a male-specific reduction in hippocampal serotonin. Administration of the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg bw) rescued the depressive-like phenotype in males exposed to lower, but not upper, dose BPA, suggesting distinct mechanisms of action for each exposure dose. Finally, high resolution mass spectrometry revealed reduced circulating levels of the neuroactive steroid dehydroepiandrosterone in BPA-exposed males, suggesting another potential mechanism underlying the depressive-like phenotype. Thus, behavioral changes associated with early life BPA exposure may be mediated by sex-specific disruptions in the serotonergic system and/or sex steroid biogenesis in male offspring.

Adult hippocampal neurogenesis is not necessary for the response to lithium in the forced swim test

“…(A two-way ANOVA on this cohort demonstrated a significant effect of lithium treatment F(1,53)=19.72, p<0.001, but no significant effect of sex F(1,53)=1.53, p=0.22 or Li treatment*sex interaction F(3,53)=1.43, p=0.24). Furthermore, prior work has demonstrated no effect of sex or estrous cycle on NPC proliferation [31] or on the FST in C57BL/6 mice [63,66], and both sexes respond to lithium in the FST [7]. Additionally, a 3-way ANOVA comparing lithium, ablation, and sex did not reveal a main effect of sex or significant interaction in our data.…”

4-tert-Octylphenol Exposure Disrupts Brain Development and Subsequent Motor, Cognition, Social, and Behavioral Functions

“…Furthermore, the abnormal behaviors induced by maternal exposure to BPA may be involved in synaptic plasticity alteration [ 31 , 32 ]. Moreover, early life exposure to BPA altered neurotransmitter systems [ 33 ]. Perinatal BPA exposure disrupts the dopaminergic and glutamatergic systems [ 34 , 35 ].…”

Brain Disorders and Chemical Pollutants: A Gap Junction Link?

“…In rodent models, offspring gestationally and/or lactationally exposed to BPA have also been reported to exhibit comparable behavioral deficits [ 534 ]. As adults, F1 male offspring of mouse dams exposed to BPA doses representative of human exposure levels, from preconception until lactation, exhibit increased depressive-like behavior [ 535 ]. Interestingly, developmental exposure of mice to BPA is associated with impaired synaptogenesis and spinogenesis, two estrogen-mediated processes that can persist into adulthood [ 536 ].…”