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Cortisol is not associated with telomere shortening or chromosomal instability in human lymphocytes cultured under low and high folate conditions.

Bull C, Christensen H, Fenech M - PLoS ONE (2015)

Bottom Line: Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions.Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate.Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth.

View Article: PubMed Central - PubMed

Affiliation: Nutritional Genomics and DNA Damage Diagnostics Laboratory, CSIRO Animal, Food and Health Sciences, Adelaide, South Australia, Australia; Department of Microbiology & Immunology, School of Molecular & Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.

ABSTRACT
Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9.1% ± 1, p = 0.02). Refuting the hypothesis, TL was consistently greater in the presence of cortisol. The effect of FA deficiency on the frequency of DNA damage was significant for nucleoplasmic bridges, circular nuclei, micronuclei and nuclear buds, (p < 0.0001-0.001). The effect of cortisol, however, was negligible, only reaching statistical significance for the frequency of fused nuclei (p = 0.04). Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions. Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate. Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth. Together these results indicate that cortisol is not directly genotoxic and that the telomere shortening associated with increased psychological stress in vivo may not be explained by a direct effect of cortisol.

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Biomarkers of DNA damage and chromosomal instability.Frequency of binucleated (BN) lymphocytes displaying one or more DNA damage biomarker (per 500 BN), following 12 days in low (25 nM) or high folic acid (FA) (100 nM) culture medium containing 0, 400, 1000 or 3500 nM cortisol: BN with (A) fused nuclei (FUS), (B) ≥1 NPB, (C) circular nuclei (CIR), (D) ≥1 MN, (E) ≥1 NBud, and (F) total frequency of BN cells containing one or more DNA damage biomarker. (mean ± SEM; 500 BN scored per duplicate slide per treatment, N = 6 participants; *represents p ≤ 0.05; VC, vehicle control).
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pone.0119367.g002: Biomarkers of DNA damage and chromosomal instability.Frequency of binucleated (BN) lymphocytes displaying one or more DNA damage biomarker (per 500 BN), following 12 days in low (25 nM) or high folic acid (FA) (100 nM) culture medium containing 0, 400, 1000 or 3500 nM cortisol: BN with (A) fused nuclei (FUS), (B) ≥1 NPB, (C) circular nuclei (CIR), (D) ≥1 MN, (E) ≥1 NBud, and (F) total frequency of BN cells containing one or more DNA damage biomarker. (mean ± SEM; 500 BN scored per duplicate slide per treatment, N = 6 participants; *represents p ≤ 0.05; VC, vehicle control).

Mentions: DNA damage was determined using the CBMN-cyt assay [34]. Consistent with the known genotoxic effect of FA deficiency the frequency of binucleated (BN) cells containing a damage biomarker was significant for nucleoplasmic bridges (NPB) (p = 0.001), circular nuclei (CIR) (p < 0.0001), micronuclei (MN) (p < 0.0001), and nuclear buds (NBud) (p = 0.0005). The effect of [cort], however, was negligible, only reaching statistical significance for the frequency of fused nuclei (FUS) (p = 0.04) (Table 2, Fig. 2).


Cortisol is not associated with telomere shortening or chromosomal instability in human lymphocytes cultured under low and high folate conditions.

Bull C, Christensen H, Fenech M - PLoS ONE (2015)

Biomarkers of DNA damage and chromosomal instability.Frequency of binucleated (BN) lymphocytes displaying one or more DNA damage biomarker (per 500 BN), following 12 days in low (25 nM) or high folic acid (FA) (100 nM) culture medium containing 0, 400, 1000 or 3500 nM cortisol: BN with (A) fused nuclei (FUS), (B) ≥1 NPB, (C) circular nuclei (CIR), (D) ≥1 MN, (E) ≥1 NBud, and (F) total frequency of BN cells containing one or more DNA damage biomarker. (mean ± SEM; 500 BN scored per duplicate slide per treatment, N = 6 participants; *represents p ≤ 0.05; VC, vehicle control).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352017&req=5

pone.0119367.g002: Biomarkers of DNA damage and chromosomal instability.Frequency of binucleated (BN) lymphocytes displaying one or more DNA damage biomarker (per 500 BN), following 12 days in low (25 nM) or high folic acid (FA) (100 nM) culture medium containing 0, 400, 1000 or 3500 nM cortisol: BN with (A) fused nuclei (FUS), (B) ≥1 NPB, (C) circular nuclei (CIR), (D) ≥1 MN, (E) ≥1 NBud, and (F) total frequency of BN cells containing one or more DNA damage biomarker. (mean ± SEM; 500 BN scored per duplicate slide per treatment, N = 6 participants; *represents p ≤ 0.05; VC, vehicle control).
Mentions: DNA damage was determined using the CBMN-cyt assay [34]. Consistent with the known genotoxic effect of FA deficiency the frequency of binucleated (BN) cells containing a damage biomarker was significant for nucleoplasmic bridges (NPB) (p = 0.001), circular nuclei (CIR) (p < 0.0001), micronuclei (MN) (p < 0.0001), and nuclear buds (NBud) (p = 0.0005). The effect of [cort], however, was negligible, only reaching statistical significance for the frequency of fused nuclei (FUS) (p = 0.04) (Table 2, Fig. 2).

Bottom Line: Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions.Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate.Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth.

View Article: PubMed Central - PubMed

Affiliation: Nutritional Genomics and DNA Damage Diagnostics Laboratory, CSIRO Animal, Food and Health Sciences, Adelaide, South Australia, Australia; Department of Microbiology & Immunology, School of Molecular & Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.

ABSTRACT
Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9.1% ± 1, p = 0.02). Refuting the hypothesis, TL was consistently greater in the presence of cortisol. The effect of FA deficiency on the frequency of DNA damage was significant for nucleoplasmic bridges, circular nuclei, micronuclei and nuclear buds, (p < 0.0001-0.001). The effect of cortisol, however, was negligible, only reaching statistical significance for the frequency of fused nuclei (p = 0.04). Cortisol was significantly associated with reduced cell division and growth and had an apparent protective effect on cell viability in the FA(low) conditions. Conclusions: Both chronic cortisol exposure, and folate deficiency, resulted in telomere elongation, however, the effect of cortisol was marginal relative to that of folate. Cortisol was not associated with increased chromosomal instability, but caused a significant reduction in cell division and growth. Together these results indicate that cortisol is not directly genotoxic and that the telomere shortening associated with increased psychological stress in vivo may not be explained by a direct effect of cortisol.

Show MeSH
Related in: MedlinePlus