Red-sided Garter

Crews discovered the important principle that sexual behavior, gamete production, and steroid hormone secretion could be dissociated, in his studies of the red-sided garter snake (T. s. parietalis). These snakes are the northernmost reptile and hibernate for much of the year, responding to temperature both to emerge from winter dormancy and to engage in sexual behavior. It was his work with this species that provided the first demonstration that the activation of sexual behavior could be independent of sex steroid hormones, depending instead upon increasing spring temperature. This work also led to the first isolation, identification and synthesis of a new class of pheromones.^[5]

Whiptail Lizard

The desert grassland whiptail lizard (A. uniparens), presented an opportunity to study first-hand how the neuroendocrine substrates underlying sexual behavior can evolve. In this instance, Crews used a parthenogenetic species derived from interbreeding of two sexual species. Remarkably, although the descendant species consists only of females, reproducing by obligate parthenogenesis, individuals continue to display sexual behaviors that are typical of both females and males, alternating behaviors depending upon their individual hormone profiles across reproductive cycles. Although it is not immediately apparent what benefit could come of females engaging in male-typical behaviors in a parthenogenetic species, Crews has shown that this behavior is important to stimulate reproduction of both individuals in these pairings.^[6]

By comparing the unisexual descendants with their sexual ancestors, Crews revealed how hormone-brain controlling mechanisms evolve. This work led to the examination of how novel hormone-brain controlling mechanisms might respond to new challenges. Of particular note is the revelation that the male-typical sexual behaviors which parthenogenetic females display turn out to be under the control of the postovulatory surge of progesterone rather than androgen, which the parthenogens do not produce. This discovery in the parthenogenetic lizard led Crews to extend his work to genetically modified mice and rats, demonstrating that progesterone is not a “female-specific” hormone but plays a critical role in sexual behavior in males. Indeed, Crews demonstrated that androgen and progesterone synergize in males to control copulatory behavior much as estrogen and progesterone synergize in females to facilitate sexual receptivity. These discoveries have shed light on recent work in humans suggesting a clinical significance of progesterone in male sexual behavior.

Temperature-dependent sex determination

Crews has been the leader in determining the physiological and molecular bases of temperature-dependent sex determination (TSD). Sex determination is a case study in how evolution has produced different mechanisms for achieving the same end. In many reptiles the sex of the offspring depends on the incubation temperature of the egg, not on genotype as in mammals. One question concerns how the physical stimulus of temperature is transduced into a molecular and physiological stimulus to determine an individual's gonadal sex. Crews demonstrated that incubation temperature acts on a group of genes homologous to those in mammals that affect gonadal differentiation.^[7] This work helped overturn the classic tenet that males are the “organized” sex and females the “default” sex. Today we recognize both sexes as organized and the question now becomes how the activation of a conserved network of genes leads to a binary response (ovary or testis).

Leopard Gecko

He is a pioneer in the relatively new field (actually rebirth) of phenotypic plasticity, or the process by which the environment induces different phenotypes from a given genotype. When considering that species without sex chromosomes possess all of the genes necessary to develop the phenotype of both sexes, it becomes apparent that the process of sex determination and sexual differentiation represents a form of phenotypic plasticity. Using the leopard gecko (E. macularius) as the animal model system, Crews determined how the experience of temperature during a narrowly defined period of embryogenesis affects the total phenotype of the adult organism, accounting for much of the variation observed among individuals in morphology, growth, endocrinology, neural activity, and neuroanatomy.^[8][9] Some sociosexual behaviors and brain measures are affected directly by incubation temperature, whereas both incubation temperature as well as gonadal sex influences others.

Transgenerational epigenetics

Crews discovered that the transgenerational epigenetic modification caused by vinclozolin exposure changes the way rats three generations removed (F3) from the original exposure perceive and react to conspecifics.^[11] This was the first demonstration that endocrine disrupting chemicals (EDCs) can promote a transgenerational alteration in the epigenome that influences sexual selection, and possibly affect the viability of a population and evolution of the species. This work was recognized by the University Cooperative Society with the 2008 Research Excellence Award for Best Research Paper, University of Texas at Austin,^[12] and was listed as one of the "Top 100 Science Stories of 2007" by Discover Magazine.^[13] Crews then extended his work into the realm of social, learning, and anxiety-related behaviors as well as the functional activity of the brain mechanisms that underlie them. His most recent work demonstrated that ancestral exposure to EDCs alters how descendants perceive and react to life challenges, in this case stress experienced during adolescence.^[14][15] Specifically, he established that environmentally induced epigenetic transgenerational inheritance alters brain development and genome activity to modify stress-induced behavioral responses exhibited by F3 males.^[16][17] This latest work has been hailed as "important paper and a paradigm shift in our understanding of the interaction between epigenetic change and behaviors."^[18]

Crews also explored the theoretical aspects of environmental epigenetics, making the important distinction between the nature of epigenetic modifications. Context-dependent epigenetic change occurs as a consequence of exposure. A defining element is that this type of change requires continued exposure to the environmental insult. For example, environmental factors that bring about an epigenetic modification may simply continue to persist. Should the diet, behavior, or a toxic environmental exposure continues across generations, the epigenetic modification will manifest in each generation. Such environmentally induced epigenetic state(s) can be reversed by removal or alteration of the factor, addition of a different environmental factor, or emigration from the contaminated site. Another form of epigenetic modification may occur when the change in the epigenome is incorporated into the germline, a process Crews has termed germline-dependent epigenetic change. In this type, the effect manifests in each generation even in the absence of the causative agent. Context-dependent epigenetic modification is fundamentally different from germline-dependent epigenetic modification. Although both have been attributed with “transgenerational” properties, only in the latter (germline) instance will the trait be passed to the next generation even in the absence of any continued exposures or stimuli. Taken together this work has generated a new perspective on the old question of ‘inherited vs experienced, ancestral vs acquired, or nature vs nurture’ and promises to shed new light on health management strategy.^[19]