In Summer 2015, the Collaborative for Southern Appalachian Studies funded a trip for Rick Wright, Carolyn Hoagland, Mark Presler, and Thea Edwards to go to Yale to learn about the Yale Farm and Sustainable Food Program.  From that trip, they generated a report that has been the basis for several innovations linking the farm and dining services.

While at Yale, Edwards met a graduate student (Lambert) who shares her research interests in botanicals that alter animal hormone systems.  From that meeting, they developed a collaboration that resulted in the attached publication, which has just been finalized.

One of the goals of the Collaborative over the past few years has been to build relationships and collaborations among colleagues at Sewanee and Yale, and we are delighted to share this example.

Beginning in the 1940s, there have been numerous reports from Australia that grazing sheep on fields of subterranean and red clover (Trifolium subterraneum and T. pretense) leads to “clover disease,” a condition of infertility that can cause lambing rates to drop by 60%–80% (Adams, 1995; Bennetts, 1944; Biggers & Curnow, 1954; Croker, Nichols, Barbetti, & Adams, 2005). Clover disease is attributed to the consumption of hormonally active phytochemicals (HAPs), particularly phytoestrogens present in clover forage (e.g., formononetin, coumestrol, genistein, and biochanin A). A ewe affected by clover disease can develop mammary gland hypertrophy, infertility, cervical deformities preventing conception, a prolapsed uterus (the uterus falls out through the vulva), or difficulty lambing. Such dramatic results have motivated development of low-HAP clover varieties in Australia. In the United Kingdom, farmers are encouraged to avoid pasturing cattle and sheep on red clover or other legumes before and during mating to prevent clover disease (Marley, McCalman, Buckingham, Downes, & Abberton, 2011). However, Marley et al. (2011) note that more specific recommendations are not yet possible due to inadequate understanding of HAP biology. According to trade publications intended for farmers, clover disease has always been rare in the United States (U.S.), in part because subterranean clover is not used in the U.S. and because animals may be fed a broader diet that includes clover in lower proportions (Hudson, 2013; Kintzel, 2013).

The need for better understanding of HAP biology inspired by clover disease has since developed into a broad toxicological research field focused on how HAPs influence reproduction in a diversity of vertebrates (Rochester & Millam, 2009; Wasserman, Milton, & Chapman, 2013). Several frameworks have emerged for conceptualizing the influence of HAPs on vertebrate reproduction (Figure 1). These hypotheses primarily focus on the role of HAPs on either plant or animal fitness. Despite different interpretations of HAP effects on vertebrates, the dominant research theme frames HAPs as harmful toxins that impair animal reproduction. How environmental context (e.g., season, drought) shapes HAP production and composition and concomitant effects on vertebrates is rarely considered. Additionally, little research attention has focused on the evolutionary consequences or adaptive potential of vertebrate HAP exposure. This is surprising because environmental influences on reproduction could reasonably affect fitness and therefore evolutionary outcomes. Here, we discuss how HAPs, modulating reproductive success, might drive evolutionary change in vertebrates.


Conceptual framework illustrating the range of hypotheses explaining evolution of HAPs, influence of HAPs on animal physiology, and fitness outcomes for both plants and animals

Historically, HAP research has focused on plant chemicals that elicit an estrogenic response (i.e., phytoestrogens) in vertebrates. However, we will consider HAPs to more broadly include plant chemicals and mixtures with agonistic or antagonistic effects on a range of endocrine outcomes including lipid metabolism, steroid or thyroid hormones, prolactin, or luteinizing hormone (Bovee, Schoonen, Hamers, Bento, & Peijnenburg, 2008; Chen & Chang, 2007; Higham, Ross, Warren, Heistermann, & MacLarnon, 2007; Ji, Domanski, Skirrow, & Helbin, 2007; Markiewicz, Garey, Adlercreutz, & Gurpide, 1993; Thompson, Wilson, Gobbo, Muller, & Pusey, 2008; Wang et al., 2015). Our review is representative of the hormonal pathways discussed in the literature, which is currently dominated by estrogenic compounds. We will explore how HAPs might fit into an evolutionary framework for vertebrates and discuss what research is needed to understand whether HAPs could act as a selective pressure for wildlife.

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