Sex-specificity in transgenerational epigenetic programming.

Prenatal programming of the epigenome is a critical determinant in offspring outcome and stands at the interface between environment and genetics. Maternal experiences such as stress and obesity are associated with a host of neurodevelopmental and metabolic diseases, some of which have been characterized into the second and third generations. The mechanism through which determinants such as maternal diet or stress contribute to disease development likely involves a complex interaction between the maternal environment, placental changes, and epigenetic programming of the embryo. While we have begun to more fully appreciate and explore the epigenome in determination of disease risk, we know little as to the contribution embryo sex makes in epigenetic regulation. This review discusses the importance of sex differences in the transmission and inheritance of traits that are generated in the prenatal environment using models of maternal stress and diet.

The epigenetics of sex differences in the brain.

Epigenetic changes in the nervous system are emerging as a critical component of enduring effects induced by early life experience, hormonal exposure, trauma and injury, or learning and memory. Sex differences in the brain are largely determined by steroid hormone exposure during a perinatal sensitive period that alters subsequent hormonal and nonhormonal responses throughout the lifespan. Steroid receptors are members of a nuclear receptor transcription factor superfamily and recruit multiple proteins that possess enzymatic activity relevant to epigenetic changes such as acetylation and methylation. Thus steroid hormones are uniquely poised to exert epigenetic effects on the developing nervous system to dictate adult sex differences in brain and behavior. Sex differences in the methylation pattern in the promoter of estrogen and progesterone receptor genes are evident in newborns and persist in adults but with a different pattern. Changes in response to injury and in methyl-binding proteins and steroid receptor coregulatory proteins are also reported. Many steroid-induced epigenetic changes are opportunistic and restricted to a single lifespan, but new evidence suggests endocrine-disrupting compounds can exert multigenerational effects. Similarly, maternal diet also induces transgenerational effects, but the impact is sex specific. The study of epigenetics of sex differences is in its earliest stages, with needed advances in understanding of the hormonal regulation of enzymes controlling acetylation and methylation, coregulatory proteins, transient versus stable DNA methylation patterns, and sex differences across the epigenome to fully understand sex differences in brain and behavior.

Long-term effect of cued fear conditioning on REM sleep microarchitecture in rats.

STUDY OBJECTIVES: To study long-term effects of conditioned fear on REM sleep (REMS) parameters in albino rats. DESIGN: We have investigated disturbances in sleep architecture, including muscle twitch density as REMS phasic activity, and freezing behavior in wakefulness, upon reexposure to a conditioned stimulus (CS) on Day 1 and Day 14 postconditioning. SUBJECTS: Male Sprague-Dawley rats prepared for polysomnographic recordings. INTERVENTIONS: After baseline sleep recording, the animals in the experimental group received five pairings of a 5-sec tone, co-terminating with a 1-sec, 1 mAfootshock. The control rats received similar numbers of tones and shocks, but explicitly unpaired. On postconditioning days, after reexposure to tones alone, sleep and freezing behavior were recorded. MEASUREMENTS AND RESULTS: Conditioned fear significantly altered REMS microarchitecture (characterized as sequential-REMS [seq-REMS: < or =3 min episode separation] and single-REMS [sin-REMS: >3 min episode separation]) on Day 14. The total amount and number of seq-REMS episodes decreased, while the total amount and number of sin-REMS episodes increased. Further, the CS induced significant increases in freezing and REMS myoclonic twitch density in the experimental group. Reexposure to the CS produced no alterations in controls. CONCLUSIONS: The results suggest that conditioned fear causes REMS alterations, including difficulty in initiating a REMS episode as indicated by the diminution in the number of seq-REMS episodes. Another finding, the increase in phasic activity, agrees with the inference from clinical investigations that retrieval of fearful memories can be associated with the long-term REMS disturbances characteristic of posttraumatic stress disorder.

Maternal high-fat diet effects on third-generation female body size via the paternal lineage.

The health consequences of in utero exposure to maternal obesity on future generations are concerning because they contribute to increased rates of diabetes, cardiovascular disease, and metabolic syndrome. We previously reported that maternal high-fat diet exposure in mice resulted in an increase in body size and reduced insulin sensitivity that persisted across two generations via both maternal and paternal lineages. However, because the first generation's primordial germ cells may be affected by gestational exposure, analysis of phenotype transmission into a third generation (F3) is necessary to determine whether stable epigenetic programming has occurred. Therefore, we have examined the body size and insulin sensitivity of male and female F3 offspring. We found that only females displayed the increased body size phenotype, and this effect was only passed on via the paternal lineage. The finding of a paternally transmitted phenotype to F3 female offspring supports a stable germline-based transgenerational mode of inheritance; thus we hypothesized that imprinted genes may be involved in this epigenetic programming. Using a quantitative TaqMan Array for imprinted genes to examine paternally or maternally expressed loci in F3 female livers, we detected a potential dynamic pattern of paternally expressed genes from the paternal lineage that was not noted in the maternal lineage. These findings suggest that the environmental influence on developmental regulation of growth and body size may be the result of broad programming events at imprinted loci, thereby providing sex specificity to both the transmission and inheritance of traits related to disease predisposition.

Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice.

Maternal obesity and diet consumption during pregnancy have been linked to offspring adiposity, cardiovascular disease, and impaired glucose metabolism. Furthermore, nutrition during development is clearly linked to somatic growth. However, few studies have examined whether phenotypes derived from maternal high-fat diet exposure can be passed to subsequent generations and by what mechanisms this may occur. Here we report the novel finding of a significant body length increase that persisted across at least two generations of offspring in response to maternal high-fat diet exposure. This phenotype is not attributable to altered intrauterine conditions or maternal feeding behavior because maternal and paternal lineages were able to transmit the effect, supporting a true epigenetic manner of inheritance. We also detected a heritable feature of reduced insulin sensitivity across two generations. Alterations in the GH secretagogue receptor (GHSR), the GHSR transcriptional repressor AF5q31, plasma IGF-I concentrations, and IGF-binding protein-3 (IGFBP3) suggest a contribution of the GH axis. These studies provide evidence that the heritability of body length and glucose homeostasis are modulated by maternal diet across multiple generations, providing a mechanism where length can increase rapidly in concert with caloric availability.