In 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."

MacLusky et al. proposed that the changes could be due to one of several mechanisms:

• direct 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,
• general 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."

To 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.

MacLusky 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.

In 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."

They 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 endocrine disruption."

The 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."

Talk to us: email