Limits...
Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior.

Skinner MK, Anway MD, Savenkova MI, Gore AC, Crews D - PLoS ONE (2008)

Bottom Line: Analysis of specific gene sets demonstrated that several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation.An investigation of behavior demonstrated that the vinclozolin F3 generation males had a decrease in anxiety-like behavior, while the females had an increase in anxiety-like behavior.Observations are discussed in regards to environmental and transgenerational influences on the etiology of brain disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, Washington, USA. Skinner@mail.wsu.edu

ABSTRACT
Embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes an epigenetic reprogramming of the male germ-line that is associated with transgenerational adult onset disease states. Further analysis of this transgenerational phenotype on the brain demonstrated reproducible changes in the brain transcriptome three generations (F3) removed from the exposure. The transgenerational alterations in the male and female brain transcriptomes were distinct. In the males, the expression of 92 genes in the hippocampus and 276 genes in the amygdala were transgenerationally altered. In the females, the expression of 1,301 genes in the hippocampus and 172 genes in the amygdala were transgenerationally altered. Analysis of specific gene sets demonstrated that several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation. An investigation of behavior demonstrated that the vinclozolin F3 generation males had a decrease in anxiety-like behavior, while the females had an increase in anxiety-like behavior. These observations demonstrate that an embryonic exposure to an environmental compound appears to promote a reprogramming of brain development that correlates with transgenerational sex-specific alterations in the brain transcriptomes and behavior. Observations are discussed in regards to environmental and transgenerational influences on the etiology of brain disease.

Show MeSH

Related in: MedlinePlus

Performance in the light:dark box in young and aged third-generation female and male rats.Data are mean±SEM of latency to enter dark (A, G), time spent in the light side of the box (B, H) and the total number of transitions made between the light and dark sides of the box (C, I) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young and aged female rats N = 8–9/group. For B aged: t15 = 2.65, p<0.018. * P<0.05, compared with control. Performance in the elevated plus-maze in young and aged third-generation female and male rats. Data are mean±SEM of percent open arm time (D, J), percent open arm entries (E, K) and total entries (F, L) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young rats, all animals from above are shown; for aged rats, N = 5 (control) and 7 (vinclozolin). The aged group represents a subset of those run in the light:dark box shown because of technical (unstable lighting) conditions during testing for the first 5 rats; these rats were omitted from the analysis. For D young: t15 = 2.30, p<0.036. For E young: t15 = 2.51, p<0.024. For D aged: t10 = 2.40, p<0.037. For E aged: t10 = 2.82, p<0.018. *P<0.05, compared with control. For young male rats, N = 9–12/group. For aged male rats, N = 9–10/group. For H young: t19 = −2.65, p<0.016. For I young: t19 = −2.46, p<0.024. * P<0.05, compared with control. All young male animals L: t19 = −3.32, p<0.004. *P<0.05, compared with control.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2581440&req=5

pone-0003745-g004: Performance in the light:dark box in young and aged third-generation female and male rats.Data are mean±SEM of latency to enter dark (A, G), time spent in the light side of the box (B, H) and the total number of transitions made between the light and dark sides of the box (C, I) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young and aged female rats N = 8–9/group. For B aged: t15 = 2.65, p<0.018. * P<0.05, compared with control. Performance in the elevated plus-maze in young and aged third-generation female and male rats. Data are mean±SEM of percent open arm time (D, J), percent open arm entries (E, K) and total entries (F, L) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young rats, all animals from above are shown; for aged rats, N = 5 (control) and 7 (vinclozolin). The aged group represents a subset of those run in the light:dark box shown because of technical (unstable lighting) conditions during testing for the first 5 rats; these rats were omitted from the analysis. For D young: t15 = 2.30, p<0.036. For E young: t15 = 2.51, p<0.024. For D aged: t10 = 2.40, p<0.037. For E aged: t10 = 2.82, p<0.018. *P<0.05, compared with control. For young male rats, N = 9–12/group. For aged male rats, N = 9–10/group. For H young: t19 = −2.65, p<0.016. For I young: t19 = −2.46, p<0.024. * P<0.05, compared with control. All young male animals L: t19 = −3.32, p<0.004. *P<0.05, compared with control.

Mentions: Experiments were initiated to extend the molecular analysis to a more behavioral level. Behavioral analyses of the control and vinclozolin F3 generation male and female animals were performed (Figure 4). A light:dark box procedure and an elevated plus-maze procedure was used to measure anxiety-like behaviors and general motor activity. Both young postnatal (P) day 70–155 (P70–155) and aged postnatal (P>200) rats were used in the analysis. In brief, there was a significant effect of sex on latency to enter dark, time on the light side, and transitions for young rats and a significant effect of sex on latency to enter dark for old rats. Previously, we demonstrated that vinclozolin F3 generation animals between 6–12 months of age develop a number of different adult onset diseases [7]. Therefore, the young P70-155 animals were selected for behavioral studies to avoid any disease artifacts. However, the aged (P>200) animals were also used for comparison with the younger animal behaviors and to better correlate with the microarray analysis. Supplemental Table S6 summarizes the performance in the light:dark box under low lighting conditions for female and male young and aged rats. In general, this condition did not appear to produce the high anxiety-like states that were found under the higher lighting conditions, based on the time spent in the light compartment.


Transgenerational epigenetic programming of the brain transcriptome and anxiety behavior.

Skinner MK, Anway MD, Savenkova MI, Gore AC, Crews D - PLoS ONE (2008)

Performance in the light:dark box in young and aged third-generation female and male rats.Data are mean±SEM of latency to enter dark (A, G), time spent in the light side of the box (B, H) and the total number of transitions made between the light and dark sides of the box (C, I) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young and aged female rats N = 8–9/group. For B aged: t15 = 2.65, p<0.018. * P<0.05, compared with control. Performance in the elevated plus-maze in young and aged third-generation female and male rats. Data are mean±SEM of percent open arm time (D, J), percent open arm entries (E, K) and total entries (F, L) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young rats, all animals from above are shown; for aged rats, N = 5 (control) and 7 (vinclozolin). The aged group represents a subset of those run in the light:dark box shown because of technical (unstable lighting) conditions during testing for the first 5 rats; these rats were omitted from the analysis. For D young: t15 = 2.30, p<0.036. For E young: t15 = 2.51, p<0.024. For D aged: t10 = 2.40, p<0.037. For E aged: t10 = 2.82, p<0.018. *P<0.05, compared with control. For young male rats, N = 9–12/group. For aged male rats, N = 9–10/group. For H young: t19 = −2.65, p<0.016. For I young: t19 = −2.46, p<0.024. * P<0.05, compared with control. All young male animals L: t19 = −3.32, p<0.004. *P<0.05, compared with control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2581440&req=5

pone-0003745-g004: Performance in the light:dark box in young and aged third-generation female and male rats.Data are mean±SEM of latency to enter dark (A, G), time spent in the light side of the box (B, H) and the total number of transitions made between the light and dark sides of the box (C, I) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young and aged female rats N = 8–9/group. For B aged: t15 = 2.65, p<0.018. * P<0.05, compared with control. Performance in the elevated plus-maze in young and aged third-generation female and male rats. Data are mean±SEM of percent open arm time (D, J), percent open arm entries (E, K) and total entries (F, L) in young (left panel) and aged (right panel) control and vinclozolin generation rats. For young rats, all animals from above are shown; for aged rats, N = 5 (control) and 7 (vinclozolin). The aged group represents a subset of those run in the light:dark box shown because of technical (unstable lighting) conditions during testing for the first 5 rats; these rats were omitted from the analysis. For D young: t15 = 2.30, p<0.036. For E young: t15 = 2.51, p<0.024. For D aged: t10 = 2.40, p<0.037. For E aged: t10 = 2.82, p<0.018. *P<0.05, compared with control. For young male rats, N = 9–12/group. For aged male rats, N = 9–10/group. For H young: t19 = −2.65, p<0.016. For I young: t19 = −2.46, p<0.024. * P<0.05, compared with control. All young male animals L: t19 = −3.32, p<0.004. *P<0.05, compared with control.
Mentions: Experiments were initiated to extend the molecular analysis to a more behavioral level. Behavioral analyses of the control and vinclozolin F3 generation male and female animals were performed (Figure 4). A light:dark box procedure and an elevated plus-maze procedure was used to measure anxiety-like behaviors and general motor activity. Both young postnatal (P) day 70–155 (P70–155) and aged postnatal (P>200) rats were used in the analysis. In brief, there was a significant effect of sex on latency to enter dark, time on the light side, and transitions for young rats and a significant effect of sex on latency to enter dark for old rats. Previously, we demonstrated that vinclozolin F3 generation animals between 6–12 months of age develop a number of different adult onset diseases [7]. Therefore, the young P70-155 animals were selected for behavioral studies to avoid any disease artifacts. However, the aged (P>200) animals were also used for comparison with the younger animal behaviors and to better correlate with the microarray analysis. Supplemental Table S6 summarizes the performance in the light:dark box under low lighting conditions for female and male young and aged rats. In general, this condition did not appear to produce the high anxiety-like states that were found under the higher lighting conditions, based on the time spent in the light compartment.

Bottom Line: Analysis of specific gene sets demonstrated that several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation.An investigation of behavior demonstrated that the vinclozolin F3 generation males had a decrease in anxiety-like behavior, while the females had an increase in anxiety-like behavior.Observations are discussed in regards to environmental and transgenerational influences on the etiology of brain disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, Washington, USA. Skinner@mail.wsu.edu

ABSTRACT
Embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes an epigenetic reprogramming of the male germ-line that is associated with transgenerational adult onset disease states. Further analysis of this transgenerational phenotype on the brain demonstrated reproducible changes in the brain transcriptome three generations (F3) removed from the exposure. The transgenerational alterations in the male and female brain transcriptomes were distinct. In the males, the expression of 92 genes in the hippocampus and 276 genes in the amygdala were transgenerationally altered. In the females, the expression of 1,301 genes in the hippocampus and 172 genes in the amygdala were transgenerationally altered. Analysis of specific gene sets demonstrated that several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation. An investigation of behavior demonstrated that the vinclozolin F3 generation males had a decrease in anxiety-like behavior, while the females had an increase in anxiety-like behavior. These observations demonstrate that an embryonic exposure to an environmental compound appears to promote a reprogramming of brain development that correlates with transgenerational sex-specific alterations in the brain transcriptomes and behavior. Observations are discussed in regards to environmental and transgenerational influences on the etiology of brain disease.

Show MeSH
Related in: MedlinePlus