David Crews

Transgenerational epigenetic imprints on mate preference

Environmental contamination by endocrine-disrupting chemicals (EDC) can have epigenetic effects (by DNA methylation) on the germ line and promote disease across subsequent generations. In natural populations, both sexes may encounter affected as well as unaffected individuals during the breeding season, and any diminution in attractiveness could compromise reproductive success. Here we examine mate preference in male and female rats whose progenitors had been treated with the antiandrogenic fungicide vinclozolin. This effect is sex-specific, and we demonstrate that females three generations removed from the exposure discriminate and prefer males who do not have a history of exposure, whereas similarly epigenetically imprinted males do not exhibit such a preference. The observations suggest that the consequences of EDCs are not just transgenerational but can be “transpopulational”, because in many mammalian species, males are the dispersing sex. This result indicates that epigenetic transgenerational inheritance of EDC action represents an unappreciated force in sexual selection. Our observations provide direct experimental evidence for a role of epigenetics as a determinant factor in evolution.

Transgenerational Epigenetic Programming of the Brain Transcriptome and Anxiety Behavior

Embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes an epigenetic reprogramming of the male germ-line that is associated with transgenerational adult onset disease states. Further analysis of this transgenerational phenotype on the brain demonstrated reproducible changes in the brain transcriptome three generations (F3) removed from the exposure. The transgenerational alterations in the male and female brain transcriptomes were distinct. In the males, the expression of 92 genes in the hippocampus and 276 genes in the amygdala were transgenerationally altered. In the females, the expression of 1,301 genes in the hippocampus and 172 genes in the amygdala were transgenerationally altered. Analysis of specific gene sets demonstrated that several brain signaling pathways were influenced including those involved in axon guidance and long-term potentiation. An investigation of behavior demonstrated that the vinclozolin F3 generation males had a decrease in anxiety-like behavior, while the females had an increase in anxiety-like behavior. These observations demonstrate that an embryonic exposure to an environmental compound appears to promote a reprogramming of brain development that correlates with transgenerational sex-specific alterations in the brain transcriptomes and behavior. Observations are discussed in regards to environmental and transgenerational influences on the etiology of brain disease.

Epigenetic transgenerational inheritance of altered stress responses

Ancestral environmental exposures have previously been shown to promote epigenetic transgenerational inheritance and influence all aspects of an individual’s life history. In addition, proximate life events such as chronic stress have documented effects on the development of physiological, neural, and behavioral phenotypes in adulthood. We used a systems biology approach to investigate in male rats the interaction of the ancestral modifications carried transgenerationally in the germ line and the proximate modifications involving chronic restraint stress during adolescence. We find that a single exposure to a common-use fungicide (vinclozolin) three generations removed alters the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress. This alteration of baseline brain development promotes a change in neural genomic activity that correlates with changes in physiology and behavior, revealing the interaction of genetics, environment, and epigenetic transgenerational inheritance in the shaping of the adult phenotype. This is an important demonstration in an animal that ancestral exposure to an environmental compound modifies how descendants of these progenitor individuals perceive and respond to a stress challenge experienced during their own life history.

Evolution of gonadotropin structure and function.

Publisher Summary It has long been recognized that the control of gonadal function by pituitary hormones (gonadotropins) is a general feature of vertebrate reproductive physiology. Numerous studies on the hormones of eutherian mammals have established the existence of two chemically distinct types of gonadotropin molecules in the pituitary-luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Recent biochemical studies on these molecules have revealed that each is a glycoprotein consisting of two chemically non-identical subunits, designated α and β. The physiological actions of the two gonadotropins in mammals are still subject to intensive investigation; however, it is agreed that FSH and LH have somewhat different roles in the regulation of gonadal function. This chapter describes a flow diagram of the protocol for the fractionation of pituitary hormones, with particular reference to gonadotropins and growth hormone (GH), from various nonmammalian species. The strong resemblance in chromatographic behavior among the fractions identified as FSH and LH from most nonmammalian species and their mammalian counterparts provided preliminary evidence of chemical similarity among the different species of FSH and of LH. Biochemical analyses on the six highly purified species of LH and FSH (chicken, turkey, alligator, snapping turtle, sea turtle, and bullfrog) yielded additional evidence for the homologies between mammalian and nonmammalian hormones.

Gamete production, sex hormone secretion, and mating behavior uncoupled

A common observation for seasonally breeding vertebrates is that the reproductive processes of gamete production, sex steroid hormone secretion, and mating behavior coincide, and further, that sex steroid hormones activate mating behavior. The postulate of hormone-dependence of mating behavior is based primarily on detailed studies of laboratory and domesticated species. However, comparison of a wide array of vertebrates reveals numerous exceptions to this supposed rule. Consideration of these species indicates that there is no fixed or intrinsic causal association among gamete production, sex hormone secretion, and mating behavior within any of the classes of vertebrates.

Temperature-Dependent Sex Determination: The Interplay of Steroid Hormones and Temperature

Abstract Sex determination is the product of coordinated gene expression. Mutational analyses have yielded great progress in our understanding of mammalian sex determination, and insight into the evolution of this sex chromosome system would be valuable. Mammals arose from turtle-like reptiles, and in many turtles the incubation temperature of the egg determines the sex of the offspring, a process known as temperature-dependent sex determination. There is mounting evidence that sex steroid hormones are the physiological equivalent of incubation temperature and serve as the proximate trigger for male and female sex determination. Temperature appears to accomplish this end by acting on genes coding for steroidogenic enzymes and sex steroid hormone receptors. The ability to manipulate sex determination in turtles both by temperature and by sex steroid hormones extends our understanding of the evolution as well as the physiology and molecular biology of sex determination.

Sex reversal by estradiol in three reptilian orders

Administration of exogenous estradiol caused embryos to develop ovaries rather than testes in alligators, softshell turtles, and leopard geckos. Alligators and leopard geckos are known to have environmental sex determination; softshell turtles lack both environmental sex determination and heteromorphic sex chromosomes. Sensitivity to gonadal feminization by estradiol thus appears to be widespread in amniotes.

Epigenetics and its implications for behavioral neuroendocrinology

Individuals vary in their sociosexual behaviors and reactivity. How the organism interacts with the environment to produce this variation has been a focus in psychology since its inception as a scientific discipline. There is now no question that cumulative experiences throughout life history interact with genetic predispositions to shape the individuals behavior. Recent evidence suggests that events in past generations may also influence how an individual responds to events in their own life history. Epigenetics is the study of how the environment can affect the genome of the individual during its development as well as the development of its descendants, all without changing the DNA sequence. Several distinctions must be made if this research is to become a staple in behavioral neuroendocrinology. The first distinction concerns perspective, and the need to distinguish and appreciate, the differences between Molecular versus Molar epigenetics. Each has its own lineage of investigation, yet both appear to be unaware of one another. Second, it is important to distinguish the difference between Context-Dependent versus Germline-Dependent epigenetic modifications. In essence the difference is one of the mechanism of heritability or transmission within, as apposed to across, generations. This review illustrates these distinctions while describing several rodent models that have shown particular promise for unraveling the contribution of genetics and the environment on sociosexual behavior. The first focuses on genetically-modified mice and makes the point that the early litter environment alters subsequent brain activity and behavior. This work emphasizes the need to understand behavioral development when doing research with such animals. The second focuses on a new rat model in which the epigenome is permanently imprinted, an effect that crosses generations to impact the descendants without further exposure to the precipitating agent. This work raises the question of how events in generations past can have consequences at both the mechanistic, behavioral, and ultimately evolutionary levels.

Social status, gonadal state, and the adrenal stress response in the lizard, Anolis carolinensis

Adult males of the small arboreal iguanid lizard, Anolis carolinensis, form social dominance hierarchies when placed in habitats with limited resources. Skin color changes occur during hierarchy formation, most conspicuously in subordinates, who appear darker (more brown) than dominants (more green). Because skin color in this species is under the control of hormones frequently associated with physiological stress, radioimmunoassay of plasma levels of the principal reptilian adrenal steroid, corticosterone, was performed. To examine the influence of gonadal androgen, known to influence the aggression that attends hierarchy formation, lizard pairs were constituted in which one or both members were castrated. Corticosterone levels of intact subordinates were significantly elevated, whereas those of castrated subordinates or dominants showed levels comparable to those of isolates. No significant differences in spermatogenic stage could be detected between intact dominants or subordinates.

Hypothalamic Arginine Vasotocin mRNA Abundance Variation Across Sexes and with Sex Change in a Coral Reef Fish

Gonadal hormones are important mediators of sexual and aggressive behavior in vertebrates. Recent evidence suggests that the peptide hormones arginine vasotocin (AVT) and its mammalian homologue arginine vasopressin (AVP) often critically mediate these gonadal hormone effects on behavior and have direct influences on behavioral variation. Behavioral differences between sexes, across reproductive states, and even among closely related species are correlated with differences in central AVT/AVP systems in many species. We report differences in hypothalamic AVT mRNA levels between distinct alternate male phenotypes and with female-to-male sex change in the bluehead wrasse (Thalassoma bifasciatum), a teleost fish. The aggressively dominant and strongly courting male phenotype has greater numbers of AVT mRNA producing cells in the magnocellular preoptic area of the hypothalamus than females. Levels of AVT mRNA within these cells in dominant males are also approximately three times female levels whereas the non-aggressive male phenotype has AVT mRNA levels approximately twice female levels. Behavioral sex change is very rapid in this species and is not dependent on the presence of gonads. Conversely, rapid increases in sexual and aggressive behavior during sex change are closely paralleled by approximate fourfold increases in hypothalamic AVT-mRNA levels. The behavioral plasticity shown by bluehead wrasses in response to social environment might be mediated in part by a neuropeptide, AVT, with changes in the gonads and gonadal hormones as the result rather than the cause of behavioral dominance.