Bisphenol-F and Bisphenol-S (BPF and BPS) Impair the Stemness of Neural Stem Cells and Neuronal Fate Decision in the Hippocampus Leading to Cognitive Dysfunctions.

ABSTRACT

Neurogenesis occurs throughout life in the hippocampus of the brain, and many environmental toxicants inhibit neural stem cell (NSC) function and neuronal generation. Bisphenol-A (BPA), an endocrine disrupter used for surface coating of plastic products causes injury in the developing and adult brain; thus, many countries have banned its usage in plastic consumer products. BPA analogs/alternatives such as bisphenol-F (BPF) and bisphenol-S (BPS) may also cause neurotoxicity; however, their effects on neurogenesis are still not known. We studied the effects of BPF and BPS exposure from gestational day 6 to postnatal day 21 on neurogenesis. We found that exposure to non-cytotoxic concentrations of BPF and BPS significantly decreased the number/size of neurospheres, BrdU+ (proliferating NSC marker) and MAP-2+ (neuronal marker) cells and GFAP+ astrocytes in the hippocampus NSC culture, suggesting reduced NSC stemness and self-renewal and neuronal differentiation and increased gliogenesis. These analogs also reduced the number of BrdU/Sox-2+, BrdU/Dcx+, and BrdU/NeuN+ co-labeled cells in the hippocampus of the rat brain, suggesting decreased NSC proliferation and impaired maturation of newborn neurons. BPF and BPS treatment increases BrdU/cleaved caspase-3+ cells and Bax-2 and cleaved caspase protein levels, leading to increased apoptosis in hippocampal NSCs. Transmission electron microscopy studies suggest that BPF and BPS also caused degeneration of neuronal myelin sheath, altered mitochondrial morphology, and reduced number of synapses in the hippocampus leading to altered cognitive functions. These results suggest that BPF and BPS exposure decreased the NSC pool, inhibited neurogenesis, induced apoptosis of NSCs, caused myelin degeneration/synapse degeneration, and impaired learning and memory in rats.