Mid to late Holocene hydrological change in continental eastern Canada: assessing regional trends from ombrotrophic peat records.

ABSTRACT High resolution records of mid-late Holocene hydro-climatic change are presented from Mer Bleue Bog, eastern Ontario. Past climatic changes in this region have previously been inferred from lake sediments, but rain-fed peatlands can offer additional insights into the spatial and temporal pattern of moisture availability. In this study, reconstructed water table depths are based on a testate amoeba-derived transfer function developed for the region and changes in bog surface wetness are compared with plant macrofossil and peat humification data.

RÉSUMÉ Nous présentons les enregistrements hautes résolutions des variations hydrologique durant la second moitié de l’Holocène pour les tourbières Mer Bleue á l’est de l'Ontario. Précédemment, les changements climatiques de cette région ont été dérivés à partir de prélèvement de sédiments de lac. Mais ils s’avèrent que les tourbières ombrotrophes offrir un éclairage supplémentaire sur les schémas de répartition spatiale et temporelle de la disponibilité de l'humidité. Dans cette étude, des profondeurs reconstruites de nappe phréatique sont basées sur un modèle de function de transfert d’amibes (Arcellinida) et des changements de l’humidité de surface de la tourbière sont comparés avec les macrofossils et au humification de tourbe dans une analyse multi-proxy.

Deregulated estrogen metabolism in BRCA1 deficient cells induces chromosomal instability.

Objectives: Germline mutations in BRCA1 predispose carriers to a high
incidence of breast and ovarian cancers. The BRCA1 protein functions to maintain
genomic stability via important roles in DNA repair, transcriptional regulation, and
post-replicative repair. Despite functions in processes essential in all cells, BRCA1
loss or mutation leads to tumours predominantly in estrogen-regulated tissues.
Here, we aim to determine if endogenous estrogen metabolites may be an initiator
of genomic instability in BRCA1 deficient cells.

Methods: We analysed DNA DSBs by ?H2AX, 53BP1, and pATM1981
foci and neutral comet assay, estrogen metabolite concentrations by LC-MS/MS,
and BRCA1 transcriptional regulation of metabolism genes by ChIP-chip, ChIP,
and qRT-PCR.

Results: We show that estrogen metabolism is perturbed in BRCA1 deficient
cells resulting in elevated production of 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2), and decreased production of the protective metabolite
4-methoxyestradiol. We demonstrate that 2-OHE2 and 4-OHE2 treatment leads
to DNA double strand breaks (DSBs) in breast cells, and these DSBs were exacerbated
in both BRCA1 depleted cells and BRCA1 heterozygous cells (harbouring
185delAG mutation). Furthermore, the DSBs were not repaired efficiently in either
BRCA1 depleted or heterozygous cells, and we found that 2-OHE2 and 4-OHE2
treatment generates chromosomal aberrations in BRCA1 depleted cells. We suggest
that the increase in DNA DSBs in BRCA1 deficient cells is due to loss of
both BRCA1 transcriptional repression of estrogen metabolising genes (such as
CYP1A1 and CYP3A4) and loss of transcriptional activation of detoxification
genes (such as COMT).

Conclusions: We suggest that BRCA1 loss results in estrogen driven tumourigenesis
through a combination of increased expression of estrogen metabolising
enzymes and reduced expression of protective enzymes, coupled with a defect in
the repair of DNA DSBs induced by endogenous estrogen metabolites. The overall
effect being an exacerbation of genomic instability in estrogen regulated tissues in
BRCA1 mutation carriers.