Systematic changes in gene expression in postmortem human brains... possible
explanation is the ratio of cortisol to DHEA
Copyright 2004, James Michael Howard, Fayetteville, Arkansas, U.S.A.
The following is the information from "Human Molecular Genetics" regarding the
findings of Li, et al., that the brain activates two different gene states
relative to the type of death of individuals. Just below is the abstract of
their article. Just below that is my explanation that this may represent the
response of the brain during "prolonged agona states"to differences in the ratio
of cortisol to DHEA.
Human Molecular Genetics Advance Access published online ahead of print January
20, 2004 Human Molecular Genetics, 10.1093/hmg/ddh065: "Systematic changes in
gene expression in postmortem human brains associated with tissue pH and
terminal medical conditions," J.Z. Li, et al., ABSTRACT: "Studies of gene
expression abnormalities in psychiatric or neurological disorders often involve
the use of postmortem brain tissue. Compared to single-cell organisms or clonal
cell lines, the biological environment and medical history of human subjects
cannot be controlled, and are often difficult to document fully. The chance of
finding significant and replicable changes depends on the nature and magnitude
of the observed variations among the studied subjects. During an analysis of
gene expression changes in mood disorders, we observed a remarkable degree of
natural variation among 120 samples, which represented three brain regions in 40
subjects. Most of such diversity can be accounted for by two distinct expression
patterns, which in turn are strongly correlated with tissue pH. Individuals who
suffered prolonged agonal states, such as with respiratory arrest, multi-organ
failure, or coma, tended to have lower pH in the brain; whereas those who
experienced brief deaths, associated with accidents, cardiac events or asphyxia,
generally had normal pH. The lower pH samples exhibited a systematic decrease in
expression of genes involved in energy metabolism and proteolytic activities,
and a consistent increase of genes encoding stress-response proteins and
transcription factors. This functional specificity of changed genes suggests
that the difference is not merely due to random RNA degradation in low pH
samples; rather it reflects a broad and actively coordinated biological response
in living cells. These findings shed light on critical molecular mechanisms that
are engaged during different forms of terminal stress, and may suggest clinical
targets of protection or restoration."
The findings of Li, et al., may have an explanation. It is my hypothesis that
dehydroepiandrosterone (DHEA) was selected by evolution because of positive
effects on all tissues, especially the brain. It followed that cortisol evolved
to counteract the effects of DHEA; I think this is the basis of the "fight or
flight mechanism" and our basic personalities These are the two major steroid
hormones of the adrenal glands. Prolonged exposure to increased levels of
cortisol produces very negative effects on the brain. I suggest this may be the
basis of Li, et al.
I suggest the "prolonged agonal states" result in severe stress or a prolonged
"fight or flight" response. In this case, the ratio of cortisol to DHEA would
predominate. DHEA is known to increase metabolism and DHEA is deficient in
schizophrenia which exhibits hypometabolism in the brain. Now, I could not find
sufficient support in the literature for this hypothesis regarding Li, et al.,
but I did find support in another area which may be applicable.
It is also my hypothesis that "intrauterine growth retardation," (IUGR) results
from insufficient DHEA for proper growth. Therefore, I would expect to see the
negative effects of cortisol in IUGR. This is, in fact, the case and the
following abstract demonstrates a similarity to the findings of Li, et al. I
suggest Li, et al., may have demonstrated a relatively prolonged effect of a
high cortisol to DHEA ratio in the brains of "individuals who suffered prolonged
agonal states" as opposed to the brains in individuals who died rapidly. (The
supporting abstract is just below.)
Pediatr Res. 2002 Jan;51(1):94-9.
Growth, IGF system, and cortisol in children with intrauterine growth
retardation: is catch-up growth affected by reprogramming of the
hypothalamic-pituitary-adrenal axis?
Cianfarani S, Geremia C, Scott CD, Germani D.
Intrauterine growth retardation (IUGR) is one of the major causes of short
stature in childhood. Although postnatal catch-up growth occurs in the majority
of IUGR children, approximately 20% of them remain permanently short. The
mechanisms that allow catch-up growth or, on the contrary, prevent IUGR children
from achieving a normal height are still unknown. Our aim was to investigate
whether intrauterine reprogramming of hypothalamic-pituitary-adrenal axis may be
involved in postnatal growth retardation of IUGR children through a modulation
of the function of the IGF system. Anthropometry, IGF system assessment,
cortisol measurement, and lipid profile evaluation were performed in 49 IUGR
children. Children were subdivided into two groups according to their actual
height corrected for midparental height: CG (catch-up growth) group, 19 children
with corrected height >or=0 z-score; and NCG (noncatch-up growth) group, 30
subjects with corrected height <0 z-score. CG children showed significantly
higher birth weight (p < 0.005) and body mass index (p < 0.05). No significant
differences in IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, soluble
IGF-II receptor levels (IGF2R), IGF-II/IGF2R ratio, and relative amounts of
IGFBP-3 circulating forms were found between CG and NCG children. None of the
IGF system-related variables correlated with anthropometric indices. NCG
children showed significantly higher concentrations of cortisol (p < 0.005) and
cortisol levels resulted inversely to birth weigh (r = -0.34, p < 0.05), birth
length (r = -0.36, p < 0.05), and corrected height (r = -0.44, p < 0.01).
Whereas total and HDL cholesterol concentrations were not significantly
different in the two groups, LDL cholesterol levels were significantly higher in
NCG children (p < 0.05), and five of 49 showed LDL cholesterol concentrations
>3.4 mM (130 mg/dL). LDL cholesterol was inversely related to birth weight (r =
-0.31, p < 0.05), corrected stature (r = -0.32, p < 0.05), and actual height (r
= -0.31, p < 0.05) and directly related to the levels of IGF2R (r = 0.44, p <
0.01). Reanalysis of 15 of 30 IUGR newborns in whom we previously reported an
inverse relationship between cord blood cortisol levels and first trimester
length gain (r = -0.54, p < 0.005) showed that the relative amount of the
IGFBP-3 18-kD fragment was related inversely to cortisol (r = -0.67, p < 0.01)
and directly to early postnatal growth (r = 0.65, p < 0.05). Our results suggest
that catch-up growth in IUGR children might be affected by intrauterine
reprogramming of hypothalamic-pituitary-adrenal axis, which may result in a
permanent modification of the neuroendocrine response to stress: children with
increased cortisol secretion may be at higher risk of growth failure. During the
neonatal period cortisol might act by limiting IGFBP-3 proteolysis and,
therefore, reducing IGF bioavailability.
