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Ozone-induced Genomic Changes in Oxidative Stress, Bioenergetics, and Glucocorticoid Signaling in Male and Female Rat Brains
Citation:
Kodavanti, Prasada Rao, D. Freeborn, P. Vulimiri, M. Valdez, AND U. Kodavanti. Ozone-induced Genomic Changes in Oxidative Stress, Bioenergetics, and Glucocorticoid Signaling in Male and Female Rat Brains. Society of Toxicology 2023 Annual Meeting, Nashville, TN, March 19 - 23, 2023.
Impact/Purpose:
This study highlights the importance of gender on the effects of Air pollutants. Current study was carried to identify some of the mechanistic aspects at genomic level in brain regions that are critical for observed neuronal effects of acute ozone exposure. Present results indicate that sex-specific responses to air pollution may, in part, be caused by difference in brain transcriptomic responses. This information may be useful for the regulatory community in determining the risk of air pollutants and influence of gender.
Description:
Recently, air pollutants (e.g., ozone [O3]) have been associated with various adverse outcomes to brain health including increased occurrence of cognitive disorders, Alzheimer’s disease, anxiety, depressive disorders, and even suicide. In the present study, we hypothesized that the sex differences underlying the increased susceptibility to inflammatory lung disease would also affect sex-specific transcription responses in brain to air pollutants. Male and female adult Long-Evans rats were exposed to O3 for 2 consecutive days (0.8 ppm, 4 hr/day), rats were euthanized, and brain regions were dissected. Protein carbonyls and various markers of oxidative stress (OS) were analyzed in the cerebellum to confirm previous results. Complexes I, II, and IV enzymes were measured in the same tissue to understand mitochondrial bioenergetics. We extended these studies to the genomic level by conducting qPCR with a panel of genes for OS, bioenergetics, and glucocorticoid signaling on hypothalamus and hippocampus, regions critical for observed neuronal effects. O3 produced more oxidative damage in the brains of females compared to males as evidenced by higher levels of protein carbonyls. Differences in mitochondrial bioenergetics may contribute to the increase in carbonyls since males showed higher levels of activity of mitochondrial complex enzymes I and IV whereas females showed increased activity of Complex II. Genes related to glucocorticoid signaling (Fkbp4, Fkbp5, Hsp90aa1, Hspa4, nr3c1, nr3c2) showed that males and females respond comparably to O3 exposure by increasing expression of glucocorticoid responsive genes. Similarly, O3 exposure decreased the expression of Bdnf in both hippocampus and hypothalamus in males and females. However, expression of genes related to mechanisms of OS (Cat, Dhcr24, Foxm1, Gpx1, Gss, Nfe2l2, Sod1) showed the most sexually dimorphic response than any other class of gene assayed. Taken together, these results indicate that sex-specific responses to air pollution may, in part, be caused by difference in brain transcriptomic responses. (This abstract does not necessarily reflect USEPA policy).