BMC Neurosci. 2001;2:20. Epub 2001 Dec 17.
Visual spatial memory is enhanced in female rats (but inhibited in males) by dietary soy phytoestrogens.
Lund TD, West TW, Tian LY, Bu LH, Simmons DL, Setchell KD, Adlercreutz H, Lephart ED.
The Neuroscience Center Brigham Young University, Provo, Utah, USA.
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BACKGROUND: In learning and memory tasks, requiring visual spatial memory (VSM), males exhibit superior performance to females (a difference attributed to the hormonal influence of estrogen). This study examined the influence of phytoestrogens (estrogen-like plant compounds) on VSM, utilizing radial arm-maze methods to examine varying aspects of memory. Additionally, brain phytoestrogen, calbindin (CALB), and cyclooxygenase-2 (COX-2) levels were determined. RESULTS: Female rats receiving lifelong exposure to a high-phytoestrogen containing diet (Phyto-600) acquired the maze faster than females fed a phytoestrogen-free diet (Phyto-free); in males the opposite diet effect was identified. In a separate experiment, at 80 days-of-age, animals fed the Phyto-600 diet lifelong either remained on the Phyto-600 or were changed to the Phyto-free diet until 120 days-of-age. Following the diet change Phyto-600 females outperformed females switched to the Phyto-free diet, while in males the opposite diet effect was identified. Furthermore, males fed the Phyto-600 diet had significantly higher phytoestrogen concentrations in a number of brain regions (frontal cortex, amygdala & cerebellum); in frontal cortex, expression of CALB (a neuroprotective calcium-binding protein) decreased while COX-2 (an inducible inflammatory factor prevalent in Alzheimer's disease) increased. CONCLUSIONS: Results suggest that dietary phytoestrogens significantly sex-reversed the normal sexually dimorphic expression of VSM. Specifically, in tasks requiring the use of reference, but not working, memory, VSM was enhanced in females fed the Phyto-600 diet, whereas, in males VSM was inhibited by the same diet. These findings suggest that dietary soy derived phytoestrogens can influence learning and memory and alter the expression of proteins involved in neural protection and inflammation in rats.

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The available research regarding cognitive function and phytoestrogens suggests that large amounts of phytoestrogens, consumed as tofu, have an adverse influence on cognitive ability in men, where decreased brain weight, increased ventricular size and dementia have been reported [44]. In ovariectomized female rats, on the other hand, phytoestrogen treatments resulted in a dose-dependent improvement of VSM [45]. This improvement in cognitive ability in phytoestrogen treated females may be due in part to the increased presence of choline acetyltransferase messenger RNA in the frontal cortex, which has been shown to be associated with protection and enhancement of cognitive function [45]. Furthermore, we have shown that phytoestrogens significantly affect the brain calcium-binding protein calbindin (CALB), which acts as a buffer by binding intracellular calcium and plays an important role in mediating cell proliferation, programmed cell death (apoptosis), and neurotoxicity [48-52]. This neuroprotective mechanism via CALB appears to be important in neurological disorders such as Parkinson's disease and Huntington's disease [48-52]. Additionally, Cyclooxygenase-2 (COX-2) seems to play an important role in mediating functional neuronal maturation and responses to certain stimuli in the brain [53-55]. The expression of COX-2 is associated with key pathophysiologic events in Alzheimer's disease: deposition of beta-amyloid protein in neuritic plaques within the hippocampus and cortex [53-55]. Of particular importance to this study is the fact that COX-2 has been shown to be influenced by steroidal hormones [53-55]. Therefore, the expression of COX-2 in the frontal cortex may also be hormonally regulated and relevant to cognitive decline.

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... In general, in all brain regions examined (except the hippocampus) Phyto-600 fed males displayed significantly higher phytoestrogen levels compared to Phyto-free fed males. In the amygdala, phytoestrogen levels were 3-fold higher in Phyto-600 males compared to Phyto-free values. Whereas, in the hippocampus there was not a significant difference between the Phyto-600 and Phyto-free fed males. However, when the frontal cortex and cerebellum were examined, where an abundance of ER-beta receptors are present, Phyto-600 males displayed a 47-fold and 9-fold higher phytoestrogens levels, respectively, compared to Phyto-free male values. In each brain site examined (except the cerebellum), the major phytoestrogen metabolite was equol and there were relatively low levels of daidzein and genistein.

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As reported, phytoestrogens were 47 times higher in the frontal cortex of Phyto-600 vs. Phyto-free fed males where there is an abundance of ER-beta receptors [2], while phytoestrogen levels were similar in these animals in the hippocampal region. Furthermore males fed the Phyto-600 diet displayed a significant decrease in frontal cortical CALB levels in comparison to males receiving the Phyto-free diet. As CALB plays an important role in regulating intraneuronal cellular calcium, which protects against neurodegenerative disease and defends against apoptosis [48-52], a decrease in frontal cortex CALB may result in cognitive impairment due to cell death or abnormal calcium homeostasis [48-52]. Furthermore, frontal cortical COX-2 was shown to significantly increase in males fed the Phyto-600 diet. Because the expression of COX-2 is associated with key pathophysiologic event(s) in Alzheimer's disease [53-55], the significant increase in COX-2 expression in the frontal cortex may be relevant to the cognitive decline seen in the Phyto-600 males. In this regard, it is known that the hormonal action of estrogens may be mediated by the differential expression of estrogen receptors alpha vs beta in brain structures that activate or inhibit cell death mechanisms [56]. Although, this parameter was not directly investigated in this study, the differing influence that dietary phytoestrogens had on CALB (significant decrease) and COX-2 (significant increase) in the male frontal cortex, suggests that phytoestrogens may activate programmed cell death. In support of this notion, since the Phyto-600 fed males displayed a 47-fold greater phytoestrogen levels in the frontal cortex (vs. Phyto-free males) and the greater affinity of phytoestrogens is for ER-beta > ER-alpha, it has been shown that estrogen-related neuronal apoptosis is determined by ER-beta and the Fas/Fas ligand system [57]. In fact isoflavones have been shown to cause apoptosis in rat primary cortical neurons in vitro via a calcium dependant mechanism [58]. Furthermore, the action of phytoestrogens may be tissue site specific. As our results show phytoestrogens are more prevalent and have greater affinity for certain brain structures and areas, therefore, phytoestrogens may act both as agonist and antagonist in a site-specific manner or in other words as natural SERM-type molecules [35,38-42].

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Finally, as established by the above findings, of particular importance which deserves emphasis is that the Phyto-600 diet, used in this study, is a typical rat chow formulation that is similar to other rodent diet products that are used in many laboratories, whereas, phytoestrogen-free (Phyto-free) diets are rarely used. As previously reported, Thigpen et al. [38] and Brown and Setchell [36] determined the source and concentration of phytoestrogens in rodent diets. The results of this study showed that phytoestrogen concentrations vary widely among diets (between 200 ėg/g and 600 ėg/g of phytoestrogens). Additionally, one of our laboratories has quantified phytoestrogen plasma levels in a variety of physiologic conditions validating the importance of soy-derived phytoestrogens via rodent chow diets [36]. Therefore not all diets have the same phytoestrogen levels, however, all diets, which have soy as their main protein source, contain phytoestrogens. It is very unusual to consider the influence of diet in hormone sensitive research investigations. This may be a critical error due to the complicating and/or confounding role phytoestrogens play. For example, we have previously shown that soy dietary phytoestrogens significantly alter body weight, food and water intake levels, puberty onset in females and prostate weights [39]. Also, we have preliminary (unpublished) data demonstrating the effects of soy-derived phytoestrogens on several endocrine and metabolic parameters. However, brain aromatase and circulating plasma estradiol levels in male rats does not appear to be influenced by dietary phytoestrogens [22,41,51]. As the results from this research imply, phytoestrogens have considerable effects on hormonally sensitive parameters and their influence may be, in part, responsible for many reported sexual dimorphisms such as, the establishment and plasticity of sexually dimorphic brain structures like the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anteroventral periventricular nucleus (AVPV) [40,41].

Therefore, dietary soy derived phytoestrogens can influence brain, cognition and memory in a manner that was previously unknown, where soy phytoestrogens enhance memory in intact females but inhibit memory in intact males. Further research is warranted in order to examine this important and growing research field of endocrine disruptors to determine the true significance of phytoestrogens influence that appears to be hormonal and gender dependent.

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Categories: 2001, Brain, Amygdala, Cerebellum, Frontal cortex, Hippocampus, Cognitive, Memory, Visual memory, Estrogen, Phytoestrogens, Hormone disruptors, Soy, Nutrition and diet