Maternal high-fat or low-protein diets promote autism-related behavior and altered social behavior within groups in offspring male mice.

Maternal malnutrition has been associated with neurodevelopmental deficits and long-term implications on the offspring's health and behavior. Here, we investigated the effects of maternal low-protein diet (LPD) or obesity-inducing maternal high-fat diet (HFD) on dyadic social interactions, group organization and autism-related behaviors in mice. We found that maternal HFD induced an autism-related behavioral phenotype in the male offspring, including a robust decrease in sociability, increased aggression, cognitive rigidity and repetitive behaviors. Maternal LPD led to a milder yet significant effect on autism-related symptoms, with no effects on olfactory-mediated social behavior. Under naturalistic conditions in a group setting, this manifested in altered behavioral repertoires, increased magnitude in dominance relations, and reduced interactions with novel social stimuli in the HFD male offspring, but not in the LPD offspring. Finally, we found HFD-induced transcriptomic changes in the olfactory bulbs of the male offspring. Together, our findings show that maternal malnutrition induces long-lasting effects on aggression and autism-related behaviors in male offspring, and potential impairments in brain regions processing chemosensory signals.

Fetal endocrine axes mRNA expression levels are related to sex and intrauterine position.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. METHODS: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. RESULTS: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males', but in the last trimester of pregnancy, male components were more related to each other than female's. CONCLUSIONS: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development.

THE EFFECT OF 4-VINYLCYCLOHEXENE DIEPOXIDE ON FEMALE NUTRIA (MYOCASTOR COYPUS) FERTILITY IN CAPTIVITY-A PILOT STUDY.

The nutria (Myocastor coypus) is a globally widespread invasive species. Attempts to eradicate nutria by shooting, poisoning, and trapping have been mostly unsuccessful, leading to calls for the development of new control methods. The compound 4-vinylcyclohexene diepoxide (VCD) is known to cause follicular atresia in mammals and may control conception when administered orally. It was hypothesized that VCD administered PO will cause follicular destruction in female nutria. VCD (250 mg/kg PO) was administered or coconut oil, as a control, to five nutria females each for 12 d. Sixty days following VCD exposure, males were introduced to the females. Over the following 7 mon, the effect of VCD on nutria fertility was assessed by conducting ultrasound monitoring to determine pregnancy status and measuring blood serum progesterone and estradiol levels. Finally, after performing ovariectomies, viable follicles were counted on histologic ovarian cortical sections. It was found that the female estrous cycles became synchronized, suggesting a Whitten effect in this species. Also, an increase in the females' serum progesterone levels following the introduction of males occurred, suggesting a male presence effect. Orally administered doses of 250 mg/kg VCD for 12 d had no significant effect on nutria pregnancy rates or on the number of follicles in the ovaries examined. Further studies, using a higher dose or longer administration period, are necessary to conclude whether orally administered VCD can be used as a contraceptive agent for nutria.

Fathers and sons, mothers and daughters: Sex-specific genetic architecture for fetal testosterone in a wild mammal.

Testosterone plays a critical role in mediating fitness-related traits in many species. Although it is highly responsive to environmental and social conditions, evidence from several species show a heritable component to its individual variation. Despite the known effects that in utero testosterone exposure have on adult fitness, the heritable component of individual testosterone variation in fetuses is mostly unexplored. Furthermore, testosterone has sex-differential effects on fetal development, i.e., a specific level may be beneficial for male fetuses but detrimental for females, producing sexual conflict. Such sexual conflict may be resolved by the evolution of a sex-specific genetic architecture of the trait. Here, we quantified fetal testosterone levels in a wild species, free-ranging nutrias (Myocastor coypus) using hair-testing and estimated testosterone heritability between parent and offspring from the same and opposite sex. We found that in utero accumulated hair testosterone levels were heritable between parents and offspring of the same sex. Moreover, there was a low additive genetic covariance between the sexes, and a low cross-sex genetic correlation, suggesting a potential for sex-specific trait evolution, expressed early on, in utero.

Paternity share predicts sons' fetal testosterone.

Multiple paternity is common in many species. While its benefits for males are obvious, for females they are less clear. Female indirect benefits may include acquiring 'good genes' for offspring or increasing litter genetic diversity. The nutria (Myocastor coypus) is a successful invasive species. In its native habitat, it is polygynous, with larger and more aggressive males monopolizing paternity. Here, using culled nutria we genetically examined multiple paternity in-utero and found a high incidence of multiple paternity and maintenance of the number of fathers throughout gestation. Moreover, male fetuses sired by the prominent male have higher testosterone levels. Despite being retained, male fetuses of 'rare' fathers, siring commonly only one of the fetuses in the litter, have lower testosterone levels. Considering the reproductive skew of nutria males, if females are selected for sons with higher future reproductive success, low testosterone male fetuses are expected to be selected against. A possible ultimate explanation for maintaining multiple paternity could be that nutria females select for litter genetic diversity e.g., a bet-hedging strategy, even at the possible cost of reducing the reproductive success of some of their sons. Reproductive strategies that maintain genetic diversity may be especially beneficial for invasive species, as they often invade through a genetic bottleneck.

Evolution of Embryo Implantation Was Enabled by the Origin of Decidual Stromal Cells in Eutherian Mammals.

Mammalian pregnancy evolved in the therian stem lineage, that is, before the common ancestor of marsupials and eutherian (placental) mammals. Ancestral therian pregnancy likely involved a brief phase of attachment between the fetal and maternal tissues followed by parturition-similar to the situation in most marsupials including the opossum. In all eutherians, however, embryo attachment is followed by implantation, allowing for a stable fetal-maternal interface and an extended gestation. Embryo attachment induces an attachment reaction in the uterus that is homologous to an inflammatory response. Here, we elucidate the evolutionary mechanism by which the ancestral inflammatory response was transformed into embryo implantation in the eutherian lineage. We performed a comparative uterine transcriptomic and immunohistochemical study of three eutherians, armadillo (Dasypus novemcinctus), hyrax (Procavia capensis), and rabbit (Oryctolagus cuniculus); and one marsupial, opossum (Monodelphis domestica). Our results suggest that in the eutherian lineage, the ancestral inflammatory response was domesticated by suppressing one of its modules detrimental to pregnancy, namely, neutrophil recruitment by cytokine IL17A. Further, we propose that this suppression was mediated by decidual stromal cells, a novel cell type in eutherian mammals. We tested a prediction of this model in vitro and showed that decidual stromal cells can suppress the production of IL17A from helper T cells. Together, these results provide a mechanistic understanding of early stages in the evolution of eutherian pregnancy.

Non-model species deliver a non-model result: Nutria female fetuses neighboring males in utero have lower testosterone.

Neighboring fetuses may impact their siblings in various respects, depending on their in utero location and sex. The effects of the intrauterine position (IUP) are widely studied in model organisms, especially laboratory bred murine strains that are characterized by short gestations and altricial offspring. In some species, the proximity to a male fetus and its higher circulating testosterone masculinizes neighboring female fetuses. In utero testosterone exposure might be manifested as higher testosterone concentrations, which contribute to a variation in morphology, reproductive potential and behavior. In this study, we examined the influence of neighboring an opposite sex fetus on testosterone levels in a feral animal model characterized by a long gestation and precocious offspring. Using necropsies of culled nutria (Myocastor coypus), we accurately determined the IUP and quantified testosterone immunoreactivity in fetal hair. We found that as expected, both male and female fetuses neighboring a male in utero had longer anogenital distance. However, females adjacent to males in utero showed lower testosterone levels than male fetuses, while testosterone levels of females without a male neighbor did not differ from those of males. This surprising result suggests an alternative mode by which local exogenous steroids may modify the local fetal environment. Our study emphasizes the importance of examining known phenomena in species with different life histories, other than the traditional murine models, to enhance our understanding of the evolutionary mechanisms that are driving sexual differentiation.

MATERNAL DEPRESSION AND CHILD OXYTOCIN RESPONSE; MODERATION BY MATERNAL OXYTOCIN AND RELATIONAL BEHAVIOR.

BACKGROUND: Maternal postpartum depression (PPD) carries long-term detrimental effects on children's well-being, yet the mechanisms of transmission remain unclear. One possible pathway of vulnerability involves the oxytocinergic (OT) system, which is transferred from mother to child via sensitive caregiving and is disrupted in PPD. METHOD: A large birth cohort (N = 1983) of women were repeatedly assessed for depression from birth to 6 years. Utilizing an extreme case design, two matched cohorts were formed; mothers chronically depressed from birth to 6 years and nondepressed controls (N = 97, depressed = 41, nondepressed; N = 56). At 6 years, mothers and children underwent psychiatric diagnosis, urinary OT was assayed from mother and child before and after social contact, and mother-child interactions were coded. RESULTS: Baseline OT and OT response of mother and child were interrelated and children of depressed mothers showed low baseline OT and attenuated OT response. Child OT response was negatively predicted by maternal depression, child Axis-I psychopathology, maternal expressed negative affect, and child social withdrawal. Interaction effect of maternal baseline OT and depression emerged. Slope analysis indicated that when maternal OT was medium or low, child OT response was negatively impacted by maternal depression. However, when maternal OT was high, child OT was unaffected, suggesting that maternal OT functionality buffers the effects of depression on the child. CONCLUSION: Results suggest involvement of the OT system in the cross-generational transfer of vulnerability, as well as resilience, from depressed mothers to their children. Because the OT system is open to interventions that enhance maternal touch and contact, findings have important implications for targeted early dyadic inventions.