Biology Reference
In-Depth Information
The direct target genes by themselves, however, are not sufficient for DNA
replication but rather prepare the cells to enter the S-phase. This is strongly
supported by the enrichment of G1/S-phase transition genes but the absence
of DNA replication genes in the microarray analysis. Likewise, the absence of
genes in GO categories related to ribosomal biogenesis and assembly in the
inhibitor-resistant TH-response genes but their presence in the genes induced
by TH alone suggest the possibility that downstream genes are required to sus-
tain cell proliferation. In addition, genes involved in apoptosis are also not sig-
nificant in TH
inhibitor-treated animals, indicating that these genes are
upregulated downstream of direct response transcription factors.
In contrast to the number of upregulated GO categories shared by TH and
TH
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þ
inhibitors versus control, little overlap was found among the signifi-
cantly enriched GO categories between the genes downregulated by TH
and the genes downregulated by TH
inhibitors. Interestingly, a number
of categories involved in cellular processes, such as cell differentiation and cy-
toskeletal changes, were significantly enriched in genes downregulated by TH
in the presence of inhibitors, whereas a number of categories at the organismal
level, such as organ development and multicellular organismal processes, were
significantly enriched in genes downregulated by TH alone. Such changes
suggest that downregulation of cellular processes occurs prior to the changes
at the organ levels and that the latter requires late/indirect TH-response genes.
Interaction of the direct TH-induced transcription factors and signaling
pathways with the premetamorphic set of transcription factors undoubtedly
contribute to tissue specificity of the TH response. Despite the presence of
TREs in their promoters, some direct TH-response genes are not expressed
in all tissues, where ST3 is restricted to fibroblasts and sonic hedgehog to
intestinal epithelium. Thus, the complement of transcription factors as well
as epigenetically modified DNA and histones determine how a tissue re-
sponds to TH. Use of microarrays to identify TH-regulated genes is a critical
step to understanding causes and consequences or tissue-specific responses to
TH, but further studies involving these genes are required to determine how
different tissues respond to the same hormone differently.
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3. ENDOCRINE DISRUPTION
3.1. Biomarkers for TH disruption
A major goal of endocrine disruption research is to identify molecular bio-
markers for detection of factors that may inhibit, mimic, or accentuate hor-
mone action. Because TH-induced morphological changes in tadpoles are
not observed before 3 days, molecular changes may serve as rapid and
