NJ, TJ Brown, S Schantz, BW Seo and RE Peterson. 1998. Hormonal
interactions in the effects of halogenated aromatic hydrocarbons of
the developing brain. Toxicology and Industrial Health 14:185-208.
this paper, MacLusky et al. summarize literature on mechanisms
involved in sexual differentiation of the brain and then present
data on impacts of fetal exposure to dioxin. R.E. Peterson's laboratory
had reported previously that exposure to extremely low doses of
dioxin in utero can alter reproductive function and behavior
subsequently in adulthood (see a summary in OSF, Chapter
7; Mably et
al. 1992a,b,c). In this paper, MacLusky et al. show that fetal
exposure to a low level of dioxin (0.7 µg/kg or 0.7 ppb) "disturbed
sexual differentiation of reproductive behavior, potentiating the
expression of feminine sexual behavior and reducing masculine behavior."
et al. proposed that the changes could be due to one of several
interference with the actions of androgen and/or estrogen during
the critical period of development,
indirect actions mediated via other receptor systems that then
modulate neuroendocrine function and thus affect development,
effects on brain development mediated via the thyroid system,
Ah receptors, or some "as yet unidentified mechanism"
which "could interfere with sexual differentiation indirectly,
by altering the extent and/or duration of the period of developmental
sensitivity to circulating androgens."
test the first of these they examine changes in brain morphology
and in the distribution of estrogen receptors in the brain. They
had predicted that the effects of dioxin on sexual behavior would
be associated with changes in the volumes of two key parts of the
brain known to be sexually dimorphic. This was not the case. Nor
did experimental treatment alter the distribution of estrogen receptors
in the brain.
et al. interpret these findings to suggest that the effects
of dioxin found are not caused by a reduction in circulating testosterone
levels, blockage of aromatase enzyme, or interfering with estrogen
action, the pathways they had expected to find implicated. Something
else is going on.
their 'Discussion and Conclusions', the authors acknowledge that
"the role of hormonal interactions in the developmental effects
of halogenated aromatic hydrocarbons (like dioxin) on the brain
remains unclear." They cite two reasons: (1) that the compounds
in question have multiple mechanisms of action and (2) that the
endpoints affected by the chemicals are "subject to extensive
regulation, through multiple hormone systems."
point out that "a number of different systems may contribute
to the developmental regulation of even the most simple reproductive
behavior pattern. The systems involved in cognitive behaviors
are clearly also sensitive to hormonal regulation, and hence to
practical consequence of this conclusion is that while it can
be clearly shown that chemicals like dioxin have significant impacts,
it may be impossible to determine with any certainty the precise
mechanism of action. "Studies of the effects of halogenated
aromatic hydrocarbons on CNS development, whether in the context
of sexual differentiation or not, are in fact unlikely to yield
simple, easily interpretable results. Changes in any one system
in the brain will almost certainly spill over into other mechanisms,
thereby initiating complex developmental events which may be hard
to predict on the basis of the known properties of the compound
under investigation. ... In dealing with HAHs, because of their
mixed and varied biochemical activities such an approach [looking
at a fairly narrow, circumscribed spectrum of biological activity]
may well generate unpredictable and occasionally baffling results."