Early Prenatal Stress Epigenetically Programs Dysmasculinization in Second-Generation Offspring via the Paternal Lineage

Abstract

Studies have linked sex-biased neurodevelopmental disorders, including autism and schizophrenia, with fetal antecedents such as prenatal stress. Further, these outcomes can persist into subsequent generations raising the possibility that aspects of heritability in these diseases involve epigenetic mechanisms. Utilizing a mouse model in which we previously identified a period in early gestation when stress results in dysmasculinized and stress-sensitive male offspring, we have examined programming effects in second-generation offspring of prenatally stressed (F2-S) or control (F2-C) sires. Examination of gene expression patterns during the perinatal sensitive period, when organizational gonadal hormones establish the sexually dimorphic brain, confirmed dysmasculinization in F2-S males where genes important in neurodevelopment showed a female-like pattern. Analyses of the epigenomic miRNA environment detected significant reductions in miR-322, miR-574, and miR-873 in the F2-S male brain, levels that were again more similar to those of control females. Increased expression of a common gene target for these 3 miRNAs, β-glycan, was confirmed in these males. These developmental effects were associated with the transmission of a stress-sensitive phenotype and shortened anogenital distance in adult F2-S males. As confirmation that the miRNA environment is responsive to organizational testosterone, neonatal males administered the aromatase inhibitor formestane exhibited dramatic changes in brain miRNA patterns, suggesting miRNAs may serve a previously unappreciated role in organizing the sexually dimorphic brain. Overall, these data support the existence of a sensitive period of early gestation when epigenetic programming of the male germline can occur, permitting transmission of specific phenotypes into subsequent generations.

Homosexuality as a Consequence of Epigenetically Canalized Sexual Development

“…Epi-marks produced at this time are therefore strong candidates for the causative agents underlying the canalization of sexually dimorphic development later in development in response to circulating androgens. The recent finding that environmentally induced epimarks that reverse sexually dimorphic brain development (i.e., feminize male development) can carryover and produce the same reversal in the following generation (Franklin et al 2010;Morgan and Bale 2011) demonstrates the potential for epi-marks laid down during very early development to influence androgen signaling later in development.…”

“…For example, we now have clear evidence that epigenetic changes to gene promoters that influence their expression (e.g., levels of CpG methylation) can be transmitted across generations (Franklin et al 2010) and that such heritable epigenetic changes can strongly influence, in the next generation, both sex-specific behavior and gene expression in the brain (Morgan and Bale 2011). As a consequence, we next apply our model of sexually antagonistic epi-marks to the human homosexual phenotype (as described in Table 1 and Figure 3).…”

Epigenetic Inheritance of Disease and Disease Risk

“…Other prenatal stressors such as infections, starvation, or hypoxia have similarly been linked to depression and neurodevelopmental disorders like schizophrenia, ADHD, and autism (Bale et al, 2010;Ronald et al, 2010). The transgenerational germline effects of prenatal stress exposure (Morgan and Bale, 2011) and the potential epigenetic mechanisms involved are further described below.…”

“…As early as during development in utero, exposure to stress can have long-term effects on brain functions. When pregnant dams are exposed to stressful conditions during gestation, their male offspring is dysmasculinized (shortened anogenital distance, reduced maletypical copulatory behavior) and is highly sensitive to stress (Ward, 1972;Morgan and Bale, 2011). The offspring of prenatally stressed males, born and raised by nonstressed females, also tend to have increased stress sensitivity and dysmasculinization (Morgan and Bale, 2011).…”

“…When pregnant dams are exposed to stressful conditions during gestation, their male offspring is dysmasculinized (shortened anogenital distance, reduced maletypical copulatory behavior) and is highly sensitive to stress (Ward, 1972;Morgan and Bale, 2011). The offspring of prenatally stressed males, born and raised by nonstressed females, also tend to have increased stress sensitivity and dysmasculinization (Morgan and Bale, 2011). In the brain of the offspring one day after birth, a shift toward a female-like expression pattern is observed for several genes important for neurodevelopment, and several microRNAs are also significantly reduced.…”