Neuroprotective and neurotoxic outcomes of androgens and estrogens in an oxidative stress environment

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dc.creatorDuong, Phong
dc.creatorTenkorang, Mavis A. A.
dc.creatorTrieu, Jenny
dc.creatorMcCuiston, Clayton
dc.creatorRybalchenko, Nataliya
dc.creatorCunningham, Rebecca L.
dc.creator.orcid0000-0001-5984-5516 (Cunningham, Rebecca)
dc.date.accessioned2022-09-06T14:39:00Z
dc.date.available2022-09-06T14:39:00Z
dc.date.issued2020-03-29
dc.description.abstractBACKGROUND: The role of sex hormones on cellular function is unclear. Studies show androgens and estrogens are protective in the CNS, whereas other studies found no effects or damaging effects. Furthermore, sex differences have been observed in multiple oxidative stress-associated CNS disorders, such as Alzheimer's disease, depression, and Parkinson's disease. The goal of this study is to examine the relationship between sex hormones (i.e., androgens and estrogens) and oxidative stress on cell viability. METHODS: N27 and PC12 neuronal and C6 glial phenotypic cell lines were used. N27 cells are female rat derived, whereas PC12 cells and C6 cells are male rat derived. These cells express estrogen receptors and the membrane-associated androgen receptor variant, AR45, but not the full-length androgen receptor. N27, PC12, and C6 cells were exposed to sex hormones either before or after an oxidative stressor to examine neuroprotective and neurotoxic properties, respectively. Estrogen receptor and androgen receptor inhibitors were used to determine the mechanisms mediating hormone-oxidative stress interactions on cell viability. Since the presence of AR45 in the human brain tissue was unknown, we examined the postmortem brain tissue from men and women for AR45 protein expression. RESULTS: Neither androgens nor estrogens were protective against subsequent oxidative stress insults in glial cells. However, these hormones exhibited neuroprotective properties in neuronal N27 and PC12 cells via the estrogen receptor. Interestingly, a window of opportunity exists for sex hormone neuroprotection, wherein temporary hormone deprivation blocked neuroprotection by sex hormones. However, if sex hormones are applied following an oxidative stressor, they exacerbated oxidative stress-induced cell loss in neuronal and glial cells. CONCLUSIONS: Sex hormone action on cell viability is dependent on the cellular environment. In healthy neuronal cells, sex hormones are protective against oxidative stress insults via the estrogen receptor, regardless of sex chromosome complement (XX, XY). However, in unhealthy (e.g., high oxidative stress) cells, sex hormones exacerbated oxidative stress-induced cell loss, regardless of cell type or sex chromosome complement. The non-genomic AR45 receptor, which is present in humans, mediated androgen's damaging effects, but it is unknown which receptor mediated estrogen's damaging effects. These differential effects of sex hormones that are dependent on the cellular environment, receptor profile, and cell type may mediate the observed sex differences in oxidative stress-associated CNS disorders.
dc.description.sponsorshipThis study was supported by the NIH R01 NS0091359 to RLC.
dc.identifier.citationDuong, P., Tenkorang, M., Trieu, J., McCuiston, C., Rybalchenko, N., & Cunningham, R. L. (2020). Neuroprotective and neurotoxic outcomes of androgens and estrogens in an oxidative stress environment. Biology of sex differences, 11(1), 12. https://doi.org/10.1186/s13293-020-0283-1
dc.identifier.issn2042-6410
dc.identifier.issue1
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31664
dc.identifier.volume11
dc.publisherBioMed Central Ltd.
dc.relation.urihttps://doi.org/10.1186/s13293-020-0283-1
dc.rights.holder© The Author(s). 2020.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceBiology of Sex Differences
dc.subjectar45
dc.subjectEstrogen
dc.subjectEstrogen receptors
dc.subjectHuman hippocampus
dc.subjectMembrane androgen receptor
dc.subjectNeurodegeneration
dc.subjectNeuroprotection
dc.subjectOxidative stress
dc.subjectSex differences
dc.subjectTestosterone
dc.subjectWindow of opportunity
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshAndrogens / pharmacology
dc.subject.meshAnimals
dc.subject.meshCell Line
dc.subject.meshEstradiol / pharmacology
dc.subject.meshEstrogens / pharmacology
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshNeuroglia / drug effects
dc.subject.meshNeuroglia / metabolism
dc.subject.meshNeurons / drug effects
dc.subject.meshNeurons / metabolism
dc.subject.meshNeuroprotection / drug effects
dc.subject.meshOxidative Stress* / drug effects
dc.subject.meshRats
dc.subject.meshReceptors, Androgen / metabolism
dc.subject.meshReceptors, Estrogen / metabolism
dc.subject.meshSex Characteristics
dc.subject.meshTestosterone / pharmacology
dc.titleNeuroprotective and neurotoxic outcomes of androgens and estrogens in an oxidative stress environment
dc.typeArticle
dc.type.materialtext

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