Integrative and Comparative Biology Advance Access originally published online on July 31, 2008
Integrative and Comparative Biology 2008 48(3):411-418; doi:10.1093/icb/icn079
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Toward a dynamic model of deposition and utilization of yolk steroids
School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA
Correspondence: 1E-mail: michael.moore{at}asu.edu
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Synopsis |
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Synopsis
IntroductionThe discovery by Schwabl that maternal steroid hormones are transferred to the egg yolk and have effects on the phenotype of offspring revealed a new pathway for non-genetic maternal effects. The initial model relied on passive transfer. The thinking was that steroids passively entered the lipophillic yolk during yolk deposition and then were deposited in the yolk until they were passively delivered to the embryo as the yolk was used. Subsequent studies revealed that the system is much more dynamic than that. Here, we explore questions about how dynamic the system really is and look at questions like: Is transfer of maternal steroids to the yolk passive or is it actively regulated? At what stages of the maternal reproductive cycle are steroids transferred? During reproduction, how dynamic are the levels of yolk steroids? Especially in the case of potentially deleterious steroids (e.g., androgens in female offspring; glucocorticoids), once deposited can they come out of the yolk over time? Can they be metabolized by the yolk or by the embryo? During incubation, how much do steroid levels in the yolk change? Can steroids diffuse from the yolk to the embryo prior to yolk utilization? Does the embryo contribute to yolk steroid levels as it develops? We believe that comprehensive answers to questions like these will eventually allow us to generate a much more accurate and complete model of the transfer and utilization of yolk steroids and that this model will be much more dynamic and active than the one initially proposed.
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Introduction |
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In his seminal article, Schwabl (1993
) provided evidence for a novel mechanism for maternal influence on offspring phenotype in oviparous animals that is not mediated by the offspring genome. Prior to this discovery, it was well known that offspring of viviparous animals were subject to maternal influence via the placenta. However, it was thought that the offspring of oviparous animals developing in the isolated egg were independent of such maternal influences. Schwabl showed that maternal steroid hormones were deposited in the egg yolk and could subsequently influence offspring phenotype. Varying levels of yolk steroids have been shown to influence a number of phenotypic characteristics of offspring, including early effects on traits like growth and begging behavior as well as long-term effects on other traits like aggression, plumage characteristics, and bird song (Schwabl 1996; Lipar and Ketterson 2000; Strasser and Schwabl 2004; Groothuis et al. 2005; Garamszegi et al. 2007).
Although many studies have documented the effects of varying amounts of maternally derived steroid hormones in yolk on the phenotype of offspring (Groothuis et al. 2005), much less attention has been paid to the mechanisms underlying these effects (Groothuis and Schwabl 2008). It is our intent in this article to use parsimony and start with the simplest biochemical explanations for the possible mechanistic pathways by which maternally derived steroid hormones could influence offspring's phenotype. We have two purposes in doing the analysis this way. First, we hope to illuminate those steps in this process that are poorly understood and especially those that seem improbable or difficult to explain by simple biochemistry alone. This will illuminate those steps in the process that require more sophisticated physiological mechanisms. Second, understanding the mechanisms underlying the influence of yolk steroids is important for understanding their adaptive significance (Lovern and Wade 2003a). If steroids are taken up in an unregulated, entirely passive manner then it is likely that their presence in yolk is simply a consequence of their lipophilic nature. Alternatively, if their uptake is regulated in some fashion, this provides a greater opportunity for adaptive responses to selection (Groothuis and Schwabl 2008).
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Simplest passive model |
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The simplest passive model relies heavily on the fact that steroid hormones are lipophillic and therefore much more soluble in yolk than in maternal plasma. In addition, steroid hormones are usually thought to freely diffuse through cell membranes and therefore have access to all cells and body compartments.
Based on these assumptions, the simple passive model proposes that steroids diffuse freely from the maternal sources to the yolking follicle while follicles are in the ovary. For lipophillic hormones like adrenal steroids and thyroid hormones that are produced at sources distant from the yolk, this transfer must occur from the plasma into the yolk. For the sex steroid hormones, which are produced in thecal and granulosa cells immediately adjacent to the yolk, this transfer could occur either via the plasma or directly from the steroidogenic cells to the yolk. These alternative pathways may have consequences for regulation (see discussion below) but the principle is the same for passive transfer since both the plasma and the cytosol are hydrophilic. Therefore, this transfer from either plasma or cytosol could be obligatory and difficult to regulate because the lipophillic steroid hormones are more soluble in the yolk. Because of this partition coefficient, at equilibrium much more steroid would be dissolved in yolk than in the aqueous plasma or cytosol.
The simple passive model also assumes that steroid deposition ceases when yolk deposition stops at ovulation. This assumption comes from the fact that no more yolk is being transferred to the oocyte and because the oocyte has lost the intimate contact with maternal capillaries and maternal steroidogenic cells that it had in the ovary. The developing egg enters the oviduct where it seems less connected to the mother.
The simplest model also assumes that steroid hormones remain at a constant concentration in the yolk throughout incubation and that they are simply delivered to the embryo as the yolk is consumed. This assumption underlies the practice of only sampling yolk steroids on the day the egg is laid. This is certainly the simplest possible mechanism, but the crucial step in which steroids are transferred from the yolk to the embryo has received very little critical attention until recently.
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A more dynamic model |
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As our understanding of yolk steroids has progressed since Schwabl's (1993
) original discovery, it has become apparent that the simple passive model may not be adequate. There are several possible components of a more dynamic model. First, transfer of steroid hormone from maternal sources to the yolk could be bidirectional. If this is true, yolk steroid levels could go up or down during deposition rather than simply accumulating over time in the yolk. Second, steroid hormone deposition in the yolk could be regulated rather than be purely passive. This would allow hormonal levels in the yolk to vary independently of maternal levels. Third, it is possible that there could be exchange of steroids between the mother and yolk after ovulation while the egg is in the oviduct. Fourth, it is possible that steroid levels change in the yolk after the egg is laid, rather than simply being used passively as the yolk is used. The most likely possibility is that steroidogenic enzymes already present in the yolk (possibly from the mother) could metabolize existing steroids or synthesize new ones from precursors. Fifth, it is possible that the yolk steroid levels reflect both maternal and embryonic contributions, especially toward the end of development. Finally, there may be active pathways by which yolk steroids are transferred from the yolk to the embryo. As we discuss below, it is particularly challenging to imagine mechanisms for delivery of steroids to the embryo from the yolk because of the tendency for the lipophillic steroids to remain in the yolk. We now examine a number of current questions that will need to be answered to better understand the issue of how dynamic the maternal-yolk–embryo transfer process is.
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Are yolk steroid concentrations at equilibrium with maternal plasma steroid concentrations? |
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Both yolk and plasma are complex mixtures of many substances, some lipophillic and some lipophobic. For our purposes of starting parsimoniously, we will make the simplifying assumptions that yolk is a pool of pure lipid whereas plasma is essentially water.
Concentrations of yolk steroids are generally higher than the concentrations in maternal plasma (Johnston and Moore 2005). Does this mean they are actively deposited? No, this is the expectation of simple equilibrium chemistry. Steroids are generally thought to be able to pass freely through the phospholipid bilayer of cell membranes. If this is the case and if steroids are more soluble in lipids than in water, at equilibrium there will be much more steroid dissolved in the lipid (yolk) than in the water (plasma). Therefore, we do not have to invoke anything other than basic chemistry to explain the transfer of steroids from plasma to yolk or their high concentration in yolk. However, is this a true equilibrium?
For this to be a true equilibrium, transport would have to be bidirectional. In addition, this question has consequences for how maternal levels of steroid hormones in plasma would be expected to relate to levels in the yolk (Fig. 1). If it is a true equilibrium with bidirectional transport, yolk levels would track maternal levels both upwardly and downwardly. Because of the solubility difference, yolk levels would always be greater, but maternal levels and yolk levels would be correlated. Alternatively, if yolk deposition is unidirectional, then steroids would accumulate constantly in the yolk and never decrease during the deposition phase. In this case, it would be the rate of steroid deposition in the yolk, not the absolute yolk levels that would correlate with maternal plasma levels (Fig. 1). In other words, deposition rates would be high when maternal levels were high and would tend to plateau when maternal levels are low.
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The best data that address this question are those on deposition of yolk steroids in layers of yolk (Lipar et al. 1999
; Bowden et al. 2001). Yolk is deposited in layers, like tree rings, that are maintained until incubation begins. Several studies have shown that the concentration of steroids in individual layers corresponds to the maternal hormone levels prevailing at the time the layer was deposited (Lipar et al. 1999; Hackl et al. 2003). This in turn suggests that once deposited in yolk, steroids are locked in place. This is consistent with the view that during deposition, yolk is actually a semi-solid matrix, not a liquid.
If the aforementioned is the case, then steroids are deposited unidirectionally and are not in equilibrium with maternal plasma. Levels of yolk steroids will not correlate with instantaneous measures of maternal steroid levels, but are more reflective of the entire history of the yolk's exposure to maternal steroids. This view is also consistent with data in birds showing that concentration of androgen in yolk increases with laying sequence order (Schwabl 1993; Lipar and Ketterson 2000; Sockman and Schwabl 2000; Groothuis and Schwabl 2002). It has been proposed that this occurs because birds lay eggs sequentially and eggs laid later have been exposed to more ovulatory surges than have those laid earlier. Thus, the hormone concentration in the egg reflects the history of exposure and is consistent with unidirectional deposition. However, in some species hormone concentrations have been found to stay constant with laying order (Ellis et al. 2001; Whittingham and Schwabl 2002) or have been found to decrease (Schwabl et al. 1997; Gil et al. 1999; Reed and Vleck 2001). In these cases, it is not clear if this reflects a different history of exposure in these species or if other mechanisms are responsible.
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Is steroid deposition into yolk active? |
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This question has been asked several times in the literature, but seemingly only when authors have not been precise about what they mean. Active transport is an energy-requiring process that usually is only applied by cells when it is necessary to move substances against a concentration gradient, or in this case against a solubility gradient. Since the cell can accomplish the transport of steroids into the yolk by passive mechanisms and can accumulate high quantities there, we think it extremely unlikely that this process employs an active, energy-requiring mechanism. However, this issue will become important when we consider how the steroids move out of the yolk to the embryo, in this case against the solubility gradient (see below).
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Is steroid deposition regulated? |
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We believe that when most people ask whether steroid deposition is active, they really mean to ask the question: is steroid deposition regulated? Since we have argued that steroid deposition is almost certainly passive, does that mean it is unregulated? No, passive processes can be regulated as easily as active ones and below we discuss possible mechanisms for the regulation of passive deposition of steroids into yolk.
The most basic mechanism for regulating deposition of steroids in to yolk is for the female to regulate her production of sex steroids. However, there are some limits to this since these hormones are also regulating basic female reproductive functions. Nevertheless, especially if yolk steroids accumulate over time due to unidirectional transfer, there are numerous ways females could vary steroid production in a way that keeps levels within the limits necessary for regulating their reproductive function but still have variable hormone levels in the yolk.
A second way to regulate transfer is to create barriers to diffusion. Although steroids are thought to diffuse freely through the lipid bilayer of cell membranes, barriers can still occur. One way to do this is with an enzymatic barrier (Licht et al. 1998). Such barriers are known to protect fetuses of viviparous species from maternal steroids (Painter et al. 2002; Painter and Moore 2005). The placenta contains high concentrations of steroid metabolizing enzymes that prevent the transfer of intact, active steroids between mother and fetus. It is conceivable that such an enzymatic barrier could surround the yolking follicle or be present in the yolk itself. Another way to influence diffusion is with membrane transporters. One well-known class of these is the p-glycoproteins (Deeken and Loscher 2007). These transporters are well known for "rejecting" steroids at the blood brain barrier (Ebinger et al. 2007). Such transporters could be present in the cell membrane of the yolking follicle itself or in the membranes of the maternal cells that surround it. Nothing is known about these transporters in yolking follicles.
Finally, it is possible that steroid deposition into yolk could be regulated by local production of steroids in the thecal and granulosa cells immediately adjacent to the developing follicle (Hackl et al. 2003). The source of the steroid hormones in the yolk is not known. It is usually assumed they diffuse into yolk from the maternal capillaries that are in intimate contact with the yolking follicle. However, the thecal and granulosa cells that are immediately adjacent to the yolking follicles produce these circulating steroids too. It is therefore possible that yolk steroids diffuse directly from these cells to the yolk. This raises the further possibility that deposition of yolk steroids could be regulated independently from the production of circulating steroids. However, this would only seem possible if there was some way for the cell to direct the diffusion of steroids and would therefore seem to require some kind of transporter, as mentioned above.
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Are yolk and maternal steroid levels coupled? |
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This question is critical and still unanswered. If steroid deposition in yolk is by unregulated passive transfer, then yolk steroid levels will reflect the cumulative history of exposure of the follicle to maternal steroids (Jawor et al. 2007
). For example, the social history of the female has been found to affect the levels of steroids deposited in eggs (Eising et al. 2008; Tanvez et al. 2008). In this simple model of unregulated passive transfer, maternal and yolk hormone levels are tightly coupled, although not instantaneously correlated (Fig. 1). Under this hypothesis, it is still possible for the female to produce variation in yolk hormone levels but this ability is severely constrained by the need for hormone production that maintains her reproductive function. This tends to support the view that yolk steroid levels are largely a simple byproduct of maternal steroid levels and of the lipophillic nature of yolk.
If steroid deposition is regulated by one of the mechanisms suggested above, then there is much greater possibility for maternal and yolk steroid levels to vary independently (Navara et al. 2006). This removes the constraint that yolk steroid levels have to track maternal production. In the absence of this constraint, for example, yolk steroid levels could increase while maternal levels are falling. This raises the possibility that yolk steroid levels have a much greater opportunity to respond adaptively to selection since yolk levels can respond to selection independently of the need to maintain maternal levels in the range necessary for successful reproduction (Groothuis and Schwabl 2008).
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Does yolk steroid deposition stop at ovulation? |
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The parsimonious passive model usually assumes that yolk steroid deposition occurs concomitantly with yolk deposition and stops at ovulation. This seems reasonable because ovulation severs the intimate contact between the maternal circulation and the yolking follicle, removes the follicle from the immediate vicinity of the steroidogenic thecal and granulosa cells, and isolates the follicle in the oviduct where deposition of albumin and a shell further isolate the egg from maternal influences. In addition, in the commonly studied birds, time in the oviduct is short, usually less than a day. For all these reasons, the possibility of postovulatory steroid deposition has generally been discounted.
The possibility of postovulatory steroid deposition should not be discounted this quickly. First, even though the egg has lost its intimate connection to the maternal circulation, steroids diffuse everywhere and are present in all compartments of the body. An intimate circulatory connection may not be necessary for deposition to take place. Second, in some non-avian taxa, especially reptiles, time in the oviduct can exceed time in the ovary by a significant amount. In most reptiles, eggs spend days and even weeks in the oviduct, not hours as in birds. This greatly increases the possibility that the eggs could accumulate additional steroid hormones; even though steroids are only present in low concentrations in the oviduct.
We (Johnston and Moore 2005) examined the possibility that steroids could be taken up into the yolk while the egg is in the oviduct in tree lizards (Urosaurus ornatus). Tree lizards are particularly interesting because they can retain eggs for several weeks during periods of drought. Because drought also causes stress in the mother, we were especially interested in whether the prolonged retention of eggs during stress could result in increased concentrations in the yolk of corticosterone, the steroid hormone produced during stress in this species. By implanting gravid females with corticosterone, we were able to show that oviductal eggs can indeed take up steroid hormones. The uptake appears to occur at only about 10–20% of the rate occurring in females with ovarian follicles, but because eggs are present in the oviduct for such a long time, significant amounts can still accumulate. Therefore, accumulation of yolk steroids requires neither intimate vascular connection nor close juxtaposition of steroid-producing cells. In these studies, significant transfer occurred in as short a time as 24 h, the shortest time employed (Johnston and Moore, unpublished data). Therefore oviductal transfer of steroids does not require lengthy contact and thus could be significant even in those taxa, like birds, that have relatively short oviductal transfer times. Together, these studies suggest that steroid transfer to eggs in the oviduct needs greater consideration in future models.
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Do yolk steroid levels change during incubation? |
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The simplest possibility is that nothing happens to steroids once they are deposited in yolk and that they remain in the yolk during incubation and are delivered to the embryo as the yolk is used up. If this is true, then it is sufficient to measure yolk steroids only on the day the egg is laid. This practice assumes that these levels reflect the embryo's exposure to hormones. However, the embryo is probably only susceptible to yolk steroids later in development when it develops receptors for steroid hormones (Bergeron et al. 1998
; Bowden et al. 2002). Are yolk steroids present long enough to have an impact on embryonic development?
In a few studies yolk steroid levels have been examined throughout incubation (Bowden et al. 2000, 2002; Jennings et al. 2000; Lovern and Wade 2001; Elf and Fivizzani 2002; Elf et al. 2002; Lovern and Wade 2003b; Bowden and Paitz 2007; Johnston et al. 2007; Paitz and Bowden 2007). In nearly all those studies, yolk steroid levels drop rather quickly during early incubation, much more rapidly than the yolk is being used. This is in direct contradiction to any passive model, in which one would expect steroids to remain in the lipophillic environment of the yolk and to become more concentrated as the yolk is used. Where do the steroids go? There are not many possibilities. They could diffuse into other compartments of the egg but this does not seem very likely since the other compartments are much more aqueous. They could be metabolized to other active forms or to inactive forms. If the steroids are converted to inactive forms, it is possible that the embryo is protected from this maternal influence. However, it is possible that they are also metabolized into active forms (see below), which may explain why effects on offspring are found in most studies despite the initial, substantial decrease in levels of yolk hormone during incubation.
Another often-detected change in levels of yolk steroids during incubation is that steroid levels often increase as hatching approaches (Jennings et al. 2000; Johnston et al. 2007). This is usually reasonably interpreted to represent an increased embryonic production of steroids. This is important for several reasons. First, it indicates that even late in development the yolk is still acting as a lipophillic sink for the uptake of steroid hormones. Second, it illustrates that yolk hormones are not solely of maternal origin; some of them are of embryonic origin as well. Third, it illustrates that late in development embryonic hormones have the potential to overwhelm maternal hormones. Since the embryo is most susceptible to hormones late in development, this could further reduce the impact of maternal hormones on embryonic development.
We need better answers to all these questions but the studies so far strongly suggest that yolk steroid levels during development are very dynamic (Fig. 2). This is contrary to simple passive models and raises important questions about how yolk steroids affect developing embryos.
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How do steroids get from the yolk to the embryo? |
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This last step in the process is the most problematic and the one perhaps most deserving of further study. During incubation, a vitelline vasculature develops that transports components of yolk from the yolk to the embryo. Yolk lipoproteins are broken down and transported in the bloodstream to be taken up by the embryo.
For steroid hormones to be transported from the yolk to the embryo, the process of deposition has to be essentially reversed. Steroid hormones have to leave the lipophillic environment of the yolk and enter the aqueous bloodstream. It seems unlikely that a simple passive model can account for this process as steroids have to be moved against a solubility gradient. It would seem that a simple passive model would predict instead that steroids would be retained in the yolk and that their concentration would increase as the yolk volume decreases. The only passive model that seems to offer hope would be one involved with steroids "hitchhiking" on yolk components being transported in the blood. However, it is still difficult to conceive what process would drive this against the concentration gradient. It is also possible that active transport could be involved, somehow using energy to move substances against a solubility gradient, but again no known mechanism for active transport of steroids has ever been found.
If we cannot get the steroids from the yolk to the embryo, it becomes difficult to explain the mechanism underlying the observed effects of yolk steroids on offspring's phenotype. However, it does not appear that yolk steroids are simply at the mercy of passive processes inside the egg. Passive models predict that steroid concentrations in yolk should increase during incubation, but most studies show they rapidly decrease (Johnston et al. 2007; Paitz and Bowden 2007). Paitz and Bowden (2007) recently proposed a clever hypothesis that resolves this conundrum. They presented evidence that yolk steroids in turtle eggs are rapidly metabolized to water-soluble metabolites, probably sulfonates. These metabolites diffuse from the lipophillic yolk to the hydrophilic albumin. This explains where the steroids go when they disappear from the yolk and how they get out of the yolk. However, water-soluble metabolites are usually thought to be inactive, so this does not explain how these steroids could affect the phenotype of the offspring. Paitz and Bowden (2007) pointed out that the sulfonation reaction is reversible, and they hypothesized that the embryo may take up sulfonated yolk steroids and convert them back to an active form.
This hypothesis is attractive because it simultaneously explains several different issues. It does, however, require further testing, especially tests demonstrating that sulfonated steroids can affect the phenotype of offspring.
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Is the embryo at the mercy of maternal steroids? |
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The two types of models explored here, the passive and the dynamic, present radically different views of the mediation of the maternal–embryo interaction via yolk steroids. In the passive model, the embryo is almost inadvertently exposed to maternal steroids largely as a result of biophysical properties of yolk and steroid hormones. This type of exposure is constrained and difficult to regulate. It seems to provide only limited opportunities for adaptive responses to selection. In contrast, the more dynamic model proposes a regulated process that requires active participation by both the mother and the embryo. This process seems much more likely to be adaptively flexible and to have greater potential for affecting the offspring's phenotype and ultimately its fitness.
In most paternal–offspring interactions, there are both common and competing interests between the mother and offspring. It seems that most of the thinking about yolk steroids has come from the underlying assumption that the mother is imposing something on a perhaps uncooperative offspring, in other words that the interaction is unidirectional. This is certainly true in the passive model. However, the dynamic model, especially the hypothesis proposed by Paitz and Bowden (2007), proposes an active role for the offspring. If the more dynamic model is accurate, it may be better to view yolk steroids as a form of transgenerational communication. The mother may be encoding information about the environment the offspring is about to face, and which the offspring can use to its advantage.
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Concluding thoughts |
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The power of integrative biology is bringing together mechanistic and evolutionary explanations to see how they illuminate each other. This is a two-way process. The study of yolk steroids provides a beautiful example of this process. The discovery that yolk steroids could have adaptive consequences for offspring's phenotypes has led to a number of mechanistic questions that would not have been asked in the absence of this observation. Conversely, as illustrated by the discussion above, the understanding of these underlying mechanisms will have consequences for understanding the adaptive significance of this effect. Future work in this area from both directions promises greater integration and is necessary if we are truly going to understand the significance of this unique pathway for transgenerational communication.
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Footnotes |
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From the symposium "Consequences of Maternally-Derived Yolk Hormones for Offspring: Current Status, Challenges and Opportunities" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 2–6, 2008, at San Antonio, Texas.
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