Offspring Phenotype Research Articles

Paternal eNOS deficiency in mice affects glucose homeostasis and liver glycogen in male offspring without inheritance of eNOS deficiency itself

Aims/hypothesisIt was shown that maternal endothelial nitric oxide synthase (eNOS) deficiency causes fatty liver disease and numerically lower fasting glucose in female wild-type offspring, suggesting that parental genetic variants may influence the offspring’s phenotype via epigenetic modifications in the offspring despite the absence of a primary genetic defect. The aim of the current study was to analyse whether paternal eNOS deficiency may cause the same phenotype as seen with maternal eNOS deficiency.MethodsHeterozygous (+/−) male eNOS (Nos3) knockout mice or wild-type male mice were bred with female wild-type mice. The phenotype of wild-type offspring of heterozygous male eNOS knockout mice was compared with offspring from wild-type parents.ResultsGlobal sperm DNA methylation decreased and sperm microRNA pattern altered substantially. Fasting glucose and liver glycogen storage were increased when analysing wild-type male and female offspring of +/− eNOS fathers. Wild-type male but not female offspring of +/− eNOS fathers had increased fasting insulin and increased insulin after glucose load. Analysing candidate genes for liver fat and carbohydrate metabolism revealed that the expression of genes encoding glucocorticoid receptor (Gr; also known as Nr3c1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1a; also known as Ppargc1a) was increased while DNA methylation of Gr exon 1A and Pgc1a promoter was decreased in the liver of male wild-type offspring of +/− eNOS fathers. The endocrine pancreas in wild-type offspring was not affected.Conclusions/interpretationOur study suggests that paternal genetic defects such as eNOS deficiency may alter the epigenome of the sperm without transmission of the paternal genetic defect itself. In later life wild-type male offspring of +/− eNOS fathers developed increased fasting insulin and increased insulin after glucose load. These effects are associated with increased Gr and Pgc1a gene expression due to altered methylation of these genes.Graphical abstract

Intergenerational Effects of Early-Life Starvation on Life History, Consumption, and Transcriptome of a Holometabolous Insect.

AbstractIntergenerational effects, also known as parental effects in which the offspring phenotype is influenced by the parental phenotype, can occur in response to factors that occur not only in early but also in late parental life. However, little is known about how these parental life stage-specific environments interact with each other and with the offspring environment to influence offspring phenotypes, particularly in organisms that realize distinct niches across ontogeny. We examined the effects of parental larval starvation and adult reproductive environment on offspring traits under matching or mismatching offspring larval starvation conditions using the holometabolous, haplodiploid insect Athalia rosae (turnip sawfly). We show that parental larval starvation had trait-dependent intergenerational effects on both life history and consumption traits of offspring larvae, partly in interaction with offspring conditions, while there was no significant effect of parental adult reproductive environment. In addition, while offspring larval starvation led to numerous gene- and pathway-level expression differences, parental larval starvation impacted far fewer genes and only the ribosomal pathway. Our findings reveal that parental starvation evokes complex intergenerational effects on offspring life history traits, consumption patterns, and gene expression, although the effects are less pronounced than those of offspring starvation.

Strong decrease in egg mass on subsequent days of oviposition generates little variation in offspring performance in the pine‐tree lappet moth, Dendrolimus pini

AbstractThe pine‐tree lappet moth, Dendrolimus pini (L.) (Lepidoptera: Lasiocampidae), is a pest whose natural range mostly follows that of its host, Scots pine, Pinus sylvestris L. (Pinaceae). Under natural conditions, we observed differences in larval body size, pointing to different rates of their growth and development. This study aimed to check whether differences in egg mass can differentiate the growth and development rate of D. pini larvae. We assumed that decrease in egg mass on subsequent days of oviposition can have a large impact. Our results indicate that there is an unusually strong fecundity advantage of large female mass in D. pini, but with each day of laying, the mean mass of the eggs decreases. However, offspring phenotype and development in D. pini is not clearly correlated with egg mass. We also confirmed a strong decrease in the number and mass of eggs on subsequent days of oviposition. However, egg mass decline did not correspond with the performance of the offspring in a laboratory rearing because the specimens formed from ‘medium‐mass’ eggs were characterized by the highest fitness. Although we noted a significant impact of the day of oviposition on some offspring's fitness parameters (e.g., development stage duration, pupal mass, adult mass), the variation was not large. The offspring hatched from eggs on the 3rd day of oviposition were characterized by increased values of some parameters (e.g., higher mass, heavier cocoons, faster development). Variation in the development of the larvae could be a strategy to help offspring survive under short‐term unfavorable conditions, and also reduces intra‐species competition which is generally beneficial.

The Transmission of Intergenerational Epigenetic Information by Sperm microRNAs.

Epigenetic information is transmitted from one generation to the next, modulating the phenotype of offspring non-genetically in organisms ranging from plants to mammals. For intergenerational non-genetic inheritance to occur, epigenetic information must accumulate in germ cells. The three main carriers of epigenetic information—histone post-translational modifications, DNA modifications, and RNAs—all exhibit dynamic patterns of regulation during germ cell development. For example, histone modifications and DNA methylation are extensively reprogrammed and often eliminated during germ cell maturation and after fertilization during embryogenesis. Consequently, much attention has been given to RNAs, specifically small regulatory RNAs, as carriers of inherited epigenetic information. In this review, we discuss examples in which microRNAs have been implicated as key players in transmitting paternal epigenetic information intergenerationally.

Unique Allergic Asthma Phenotypes in Offspring of House Dust Mite-exposed Mice.

Asthma is a heterogeneous inflammatory airway disease that develops in response to a combination of genetic predisposition and environmental exposures. Patients with asthma are grouped into phenotypes with shared clinical features and biomarker profiles to help tailor specific therapies. However, factors driving development of specific phenotypes are poorly understood. Prenatal exposure to maternal asthma is a unique risk factor for childhood asthma. Here we tested whether maternal asthma skews asthma phenotypes in offspring. We compared airway hyperreactivity and inflammatory and neurotrophin lung signatures before and after allergen challenge in offspring born to mice exposed to house dust mite (HDM) or vehicle during pregnancy. Maternal HDM exposure potentiated offspring responses to HDM allergen, significantly increasing both airway hyperreactivity and airway eosinophilia compared with control mice. Maternal HDM exposure broadly skewed the offspring cytokine response from a classic allergen-induced T-helper cell type 2 (Th2)-predominant signature in HDM-treated offspring of vehicle-exposed mothers, toward a mixed Th17/Th1 phenotype in HDM-treated offspring of HDM-exposed mothers. Morphologic analysis determined that maternal HDM exposure also increased airway epithelial sensory nerve density and induced distinct neurotrophin signatures to support airway hyperinnervation. Our results demonstrate that maternal allergen exposure alters fetal lung development and promotes a unique inflammatory phenotype at baseline and in response to allergen that persists into adulthood.

Different ecological histories of sea urchins acclimated to reduced pH influence offspring response to multiple stressors

End-of-the-century predictions on carbon dioxide (CO2) driven ocean acidification and the continuous leakage of pesticides from inland to coastal areas are of concern for potential negative effects on marine species' early life stages which are the most vulnerable to environmental changes. Variations in seawater chemistry related to human activities may interfere with the normal development from embryo to juvenile/adult stage. However, transgenerational studies suggest that the parental generation can influence the offspring phenotype, and thus their performances, based on the environment experienced. Here we compared the transgenerational responses to a multiple stressor scenario in sea urchins (Paracentrotus lividus) that experienced different environments since their settlement: i.e., animals from a highly variable environment, such as the Venice lagoon, versus animals from a coastal area with prevailing oligotrophic conditions in the Northern Adriatic Sea. After long-term maintenance (2 and 6 months) of adult sea urchins at natural and −0.4 units reduced pH, the F1 generations were obtained. Embryos were reared under four experimental conditions: natural and −0.4 pH both in the absence and in the presence of an emerging contaminants’ mixture (glyphosate and aminomethylphosphonic acid at environmentally relevant concentrations, 100 μg/L). A significant detrimental effect of both the parental and the filial pH was highlighted, affecting embryo development and growth. Nonetheless, sea urchins from both sites were able to cope with ocean acidification. The 6-months F1 response was better than that of the 2-months F1. Conversely, the F1 response of the sea urchins maintained at natural conditions did not change sensibly after more prolonged parental exposure. An additive but mild negative effect of the mixture was observed, mostly in lagoon offspring. Results suggest that long-term exposure to reduced pH leads to transgenerational acclimation but does not affect susceptibility to the tested pollutants.

Transgenerational effects of grandparental and parental diets combine with early-life learning to shape adaptive foraging phenotypes in Amblyseius swirskii

Transgenerational effects abound in animals. While a great deal of research has been dedicated to the effects of maternal stressors such as diet deficiency, social deprivation or predation risk on offspring phenotypes, we have a poor understanding of the adaptive value of transgenerational effects spanning across multiple generations under benign conditions and the relative weight of multigenerational effects. Here we show that grandparental and parental diet experiences combine with personal early-life learning to form adaptive foraging phenotypes in adult plant-inhabiting predatory mites Amblyseius swirskii. Our findings provide insights into transgenerational plasticity caused by persistent versus varying conditions in multiple ancestral generations and show that transgenerational effects may be adaptive in non-matching ancestor and offspring environments.

Maternal and paternal sugar consumption interact to modify offspring life history and physiology

Abstract Intergenerational effects on offspring phenotypes occur in response to variation in both maternal and paternal nutrition. Because the combined maternal and paternal effects are rarely considered together, however, their relative contributions, and the capacity for interactions between parental diets to shape offspring life history and physiology are not understood. To address this, we altered the sucrose levels of adult fruit flies (Drosophila melanogaster) prior to mating, across two generations, producing parent–parent and parent–offspring combinations that were either matched or mismatched in dietary sucrose. We then measured life span, fecundity, body mass and triglyceride levels in parents and offspring. We reveal complex, non‐cumulative interactions, which involve diets of each parent and offspring, shape offspring phenotypes, but the effects were generally not consistent with an adaptive response to parental diet. Notably, we find that interacting parental flies (sires and dams) lived longer when their sucrose treatments were matched, but they produced shorter lived offspring. These results are suggestive of intergenerational conflict over optimal diets, and call for further research into the capacity, and mechanisms, for mismatches in parental environments to enhance offspring phenotype generally. Our study also indicates that studies of maternal and paternal effects will need embrace experimental designs with power to test for interactions between maternal and paternal environments if they are to fully understand the ecological and evolutionary significance of parental effects on offspring fitness. Read the free Plain Language Summary for this article on the Journal blog.

Predicting selection-response gradients of heat tolerance in a widespread reef-building coral.

Ocean temperatures continue to rise owing to climate change, but it is unclear whether heat tolerance of marine organisms will keep pace with warming. Understanding how tolerance scales from individuals to species and quantifying adaptive potentials is essential to forecasting responses to warming. We reproductively crossed corals from a globally distributed species (Acropora tenuis) on the Great Barrier Reef (Australia) from three thermally distinct reefs to create 85 offspring lineages. Individuals were experimentally exposed to temperatures (27.5, 31 and 35.5°C) in adult and two critical early life stages (larval and settlement) to assess acquired heat tolerance via outcrossing of offspring phenotypes by comparing five physiological responses (photosynthetic yields, bleaching, necrosis, settlement and survival). Adaptive potentials and physiological reaction norms were calculated across three stages to integrate heat tolerance at different biological scales. Selective breeding improved larval survival to heat by 1.5-2.5× but did not result in substantial enhancement of settlement, although population crosses were significantly different. Under heat stress, adults were less variable compared with larval responses in warmer reefs than in the cooler reef. Adults and offspring also differed in their mean population responses, likely underpinned by heat stress imposing strong divergent selection on adults. These results have implications for downstream selection during reproduction, evidenced by variability in a conserved heat tolerance response across offspring lineages. These results inform our ability to forecast the impacts of climate change on wild populations of corals and will aid in developing novel conservation tools such as the assisted evolution of at-risk species.

Antidepressant-like activity of gestational administration of vitamin D is suppressed by prenatal overexposure to dexamethasone in female Wistar rats

Overexposure to glucocorticoids during gestation can lead to long-term mental disorders. Given the higher prevalence of depression in females, we investigated whether late gestational administration of dexamethasone could generate a depressive-like phenotype in the adult female offspring and if vitamin D could have a neuroprotective effect in this context. Pregnant rats received vitamin D (VitD, 500 IU/day) or vehicle (CTL) during gestation. Other pregnant rats received dexamethasone (Dex 0.1 mg/kg/ - 14th to the 19th gestational day) or dexamethasone + vitamin D (DexVitD). The offspring were tested for anhedonia (sucrose preference) and depressive-like behavior (forced swimming test) at postnatal months (PNM) 3, 6 and 12. Components of the serotonergic system, as well as glucocorticoids’ receptors, were evaluated in the dorsal raphe nucleus at PNM 6 and 12. Prenatal vitamin D and dexamethasone increased sucrose preference at PNM 12. Prenatal vitamin D had an antidepressant-like effect at PNM 3 in rats overexposed to dexamethasone. However, at PNM 12, this effect was blunted in the DexVitD group. Prenatal dexamethasone reduced the protein content of SERT, TPH, and 5-HT1A receptors in the dorsal raphe nucleus at 6 but not at 12 PNM. The glucocorticoids’ receptors expression was similar in all groups. We concluded that prenatal overexposure to dexamethasone does not change emotional behaviors in females, but it blunts the antidepressant-like effect of gestational vitamin D in an age-dependent manner. The antidepressant-like activity of vitamin D in the offspring was not related either to alterations of the serotonergic system or the glucocorticoids’ receptors expression in the dorsal raphe nucleus.

Early programming of reproductive health and fertility: novel neuroendocrine mechanisms and implications in reproductive medicine.

BACKGROUNDAccording to the Developmental Origins of Health and Disease (DOHaD) hypothesis, environmental changes taking place during early maturational periods may alter normal development and predispose to the occurrence of diverse pathologies later in life. Indeed, adverse conditions during these critical developmental windows of high plasticity have been reported to alter the offspring developmental trajectory, causing permanent functional and structural perturbations that in the long term may enhance disease susceptibility. However, while solid evidence has documented that fluctuations in environmental factors, ranging from nutrient availability to chemicals, in early developmental stages (including the peri-conceptional period) have discernible programming effects that increase vulnerability to develop metabolic perturbations, the impact and eventual mechanisms involved, of such developmental alterations on the reproductive phenotype of offspring have received less attention.OBJECTIVE AND RATIONALEThis review will summarize recent advances in basic and clinical research that support the concept of DOHaD in the context of the impact of nutritional and hormonal perturbations, occurring during the periconceptional, fetal and early postnatal stages, on different aspects of reproductive function in both sexes. Special emphasis will be given to the effects of early nutritional stress on the timing of puberty and adult gonadotropic function, and to address the underlying neuroendocrine pathways, with particular attention to involvement of the Kiss1 system in these reproductive perturbations. The implications of such phenomena in terms of reproductive medicine will also be considered.SEARCH METHODSA comprehensive MEDLINE search, using PubMed as main interface, of research articles and reviews, published mainly between 2006 and 2021, has been carried out. Search was implemented using multiple terms, focusing on clinical and preclinical data from DOHaD studies, addressing periconceptional, gestational and perinatal programming of reproduction. Selected studies addressing early programming of metabolic function have also been considered, when relevant.OUTCOMESA solid body of evidence, from clinical and preclinical studies, has documented the impact of nutritional and hormonal fluctuations during the periconceptional, prenatal and early postnatal periods on pubertal maturation, as well as adult gonadotropic function and fertility. Furthermore, exposure to environmental chemicals, such as bisphenol A, and maternal stress has been shown to negatively influence pubertal development and gonadotropic function in adulthood. The underlying neuroendocrine pathways and mechanisms involved have been also addressed, mainly by preclinical studies, which have identified an, as yet incomplete, array of molecular and neurohormonal effectors. These include, prominently, epigenetic regulatory mechanisms and the hypothalamic Kiss1 system, which likely contribute to the generation of reproductive alterations in conditions of early nutritional and/or metabolic stress. In addition to the Kiss1 system, other major hypothalamic regulators of GnRH neurosecretion, such as γ-aminobutyric acid and glutamate, may be targets of developmental programming.WIDER IMPLICATIONSThis review addresses an underdeveloped area of reproductive biology and medicine that may help to improve our understanding of human reproductive disorders and stresses the importance, and eventual pathogenic impact, of early determinants of puberty, adult reproductive function and fertility.

Sperm histone H3 lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction

ObjectiveParental environmental exposures can strongly influence descendant risks for adult disease. How paternal obesity changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. The objective of this study was to assess (1) whether obesity induced by a high-fat diet alters sperm histone methylation; (2) whether paternal obesity can induce metabolic disturbances across generations; (3) whether there could be cumulative damage to the sperm epigenome leading to enhanced metabolic dysfunction in descendants; and (4) whether obesity-sensitive regions associate with embryonic epigenetic and transcriptomic profiles. Using a genetic mouse model of epigenetic inheritance, we investigated the role of histone H3 lysine 4 methylation (H3K4me3) in the paternal transmission of metabolic dysfunction. This transgenic mouse overexpresses the histone demethylase enzyme KDM1A in the developing germline and has an altered sperm epigenome at the level of histone H3K4 methylation. We hypothesized that challenging transgenic sires with a high-fat diet would further erode the sperm epigenome and lead to enhanced metabolic disturbances in the next generations. MethodsTo assess whether paternal obesity can have inter- or transgenerational impacts, and if so to identify potential mechanisms of this non-genetic inheritance, we used wild-type C57BL/6NCrl and transgenic males with a pre-existing altered sperm epigenome. To induce obesity, sires were fed either a control or high-fat diet (10% or 60% kcal fat, respectively) for 10–12 weeks, then bred to wild-type C57BL/6NCrl females fed a regular diet. F1 and F2 descendants were characterized for metabolic phenotypes by examining the effects of paternal obesity by sex, on body weight, fat mass distribution, the liver transcriptome, intraperitoneal glucose, and insulin tolerance tests. To determine whether obesity altered the F0 sperm chromatin, native chromatin immunoprecipitation-sequencing targeting H3K4me3 was performed. To gain insight into mechanisms of paternal transmission, we compared our sperm H3K4me3 profiles with embryonic and placental chromatin states, histone modification, and gene expression profiles. ResultsObesity-induced alterations in H3K4me3 occurred in genes implicated in metabolic, inflammatory, and developmental processes. These processes were associated with offspring metabolic dysfunction and corresponded to genes enriched for H3K4me3 in embryos and overlapped embryonic and placenta gene expression profiles. Transgenerational susceptibility to metabolic disease was only observed when obese F0 had a pre-existing modified sperm epigenome. This coincided with increased H3K4me3 alterations in sperm and more severe phenotypes affecting their offspring. ConclusionsOur data suggest sperm H3K4me3 might serve as a metabolic sensor that connects paternal diet with offspring phenotypes via the placenta. This non-DNA-based knowledge of inheritance has the potential to improve our understanding of how environment shapes heritability and may lead to novel routes for the prevention of disease. This study highlights the need to further study the connection between the sperm epigenome, placental development, and children's health. Summary sentencePaternal obesity impacts sperm H3K4me3 and is associated with placenta, embryonic and metabolic outcomes in descendants.

The behavioural and physiological ecology of embryos: responding to the challenges of life inside an egg

Adaptations of post-hatching animals have attracted far more study than have embryonic responses to environmental challenges, but recent research suggests that we have underestimated the complexity and flexibility of embryos. We advocate a dynamic view of embryos as organisms capable of responding - on both ecological and evolutionary timescales - to their developmental environments. By viewing embryos in this way, rather than assuming an inability of pre-hatching stages to adapt and respond, we can broaden the ontogenetic breadth of evolutionary and ecological research. Both biotic and abiotic factors affect embryogenesis, and embryos exhibit a broad range of behavioural and physiological responses that enable them to deal with changes in their developmental environments in the course of interactions with their parents, with other embryos, with predators, and with the physical environment. Such plasticity may profoundly affect offspring phenotypes and fitness, and in turn influence the temporal and spatial dynamics of populations and communities. Future research in this field could benefit from an integrated framework that combines multiple approaches (field investigations, manipulative experiments, ecological modelling) to clarify the mechanisms and consequences of embryonic adaptations and plasticity.

Spatial bet hedging, thermal trade-offs and glyphosate: crickets integrate multivariate information during oviposition

Animals are increasingly exposed to thermal and chemical stressors across spatially heterogeneous landscapes, and adaptive reproductive decisions may mitigate the effects of multiple stressors. Yet, the combined effects of temperature and glyphosate (a broad-spectrum herbicide that is potentially the most commonly used pesticide worldwide) on maternal decision making and terrestrial embryos are unknown. Here, we integrate the effects of temperature, glyphosate (alone and in its commercial formulation, Roundup®) and spatial heterogeneity on oviposition (egg-laying) behaviour, which affects the fitness of females and their offspring. We used the variable field cricket, Gryllus lineaticeps , to test several hypotheses explaining oviposition site selection, specifically the roles of embryo survival, offspring phenotype and maternal survival in oviposition decisions. Temperature (but not glyphosate) affected oviposition and offspring success, with higher performance at intermediate temperatures and lower performance at the extremes, and oviposition increased with the availability of oviposition sites, particularly at warmer temperatures. Environmental context influenced support for oviposition site selection hypotheses. For example, spatial bet hedging (putatively related to maternal survival) was temperature sensitive and it modulated support for the ‘offspring phenotype’ and ‘embryo survival’ hypotheses. Specifically, an increased availability of oviposition sites prompted females to oviposit at warmer temperatures, thereby favouring offspring phenotype (increased developmental rate) at an expense to embryo survival (reduced hatching success). In summary, the interconnectedness of spatial and thermal heterogeneity (but not a common pesticide) played large roles in decision making that affects transgenerational fitness. • We tested hypotheses for oviposition (egg laying) site selection in G. lineaticeps. • We examined effects of temperature, glyphosate and spatial heterogeneity. • More numerous and warmer sites favoured developmental rate, not embryo survival. • Temperature influenced spatial bet hedging during egg laying. • Regardless of temperature, glyphosate did not affect egg laying or embryos.

Advanced paternal age increased metabolic risks in mice offspring

ObjectivesThe Developmental Origins of Health and Disease Science indicate that chronic diseases in adulthood are associated with prenatal and early-life traits. Our study aimed to explore the metabolic phenotype of offspring from advanced paternal age (APA) and the inherited alterations in sperm. Methods3-month-old (Young father, YF-F0) and 21-month-old male (Old Father, OF-F0) C57BL/6J mice were used to study paternal aging's effect on offspring. Blood glucose testing, lipid analysis, indirect calorimetry and RNA sequencing were performed. ResultsThe characterized metabolic changes in OF-F1 male mice offspring were glucose intolerance, hepatic lipid accumulation, increased adipocytes and impaired energy balance that lasted until they were elderly. Gene expression in both 8-week-old and 52-week-old offspring livers significantly altered in lipid metabolism- and thermogenesis-related pathways. PPAR signaling pathway was activated in both young and elderly offspring livers as indicated by significant upregulation of Cyp7a1, Cyp8b1, Cyp4a10, Cyp4a31, Fabp2, and Scd1. These targeted genes were also confirmed to be increased in offspring adipocytes. Furthermore, when examined the differentially expressed genes in F0 and F1 sperm, upregulated pathways including cholesterol metabolism, type II diabetes mellitus and endocrine resistance were strongly related to the APA offspring phenotype. Importantly, approximately 46.7% of enriched pathways in the sperm of APA offspring were consistent with those of APA fathers. ConclusionsThese findings added evidence of the connection between paternal gametes and alterations in progeny genome and raised the possibility that inherited alterations in sperm contribute to the intergenerational effects of paternal aging offspring's chronic metabolic risks.

A feature of maternal sleep apnea during gestation causes autism-relevant neuronal and behavioral phenotypes in offspring.

Mounting epidemiologic and scientific evidence indicates that many psychiatric disorders originate from a complex interplay between genetics and early life experiences, particularly in the womb. Despite decades of research, our understanding of the precise prenatal and perinatal experiences that increase susceptibility to neurodevelopmental disorders remains incomplete. Sleep apnea (SA) is increasingly common during pregnancy and is characterized by recurrent partial or complete cessations in breathing during sleep. SA causes pathological drops in blood oxygen levels (intermittent hypoxia, IH), often hundreds of times each night. Although SA is known to cause adverse pregnancy and neonatal outcomes, the long-term consequences of maternal SA during pregnancy on brain-based behavioral outcomes and associated neuronal functioning in the offspring remain unknown. We developed a rat model of maternal SA during pregnancy by exposing dams to IH, a hallmark feature of SA, during gestational days 10 to 21 and investigated the consequences on the offspring's forebrain synaptic structure, synaptic function, and behavioral phenotypes across multiples stages of development. Our findings represent a rare example of prenatal factors causing sexually dimorphic behavioral phenotypes associated with excessive (rather than reduced) synapse numbers and implicate hyperactivity of the mammalian target of rapamycin (mTOR) pathway in contributing to the behavioral aberrations. These findings have implications for neuropsychiatric disorders typified by superfluous synapse maintenance that are believed to result, at least in part, from largely unknown insults to the maternal environment.

Maternal age and maternal environment affect egg composition, yolk testosterone, offspring growth and behaviour in laying hens

Maternal effects have been reported to alter offspring phenotype in laying hens. In this study, we investigated the effects of maternal environment and maternal age on egg traits and offspring development and behaviour. For this, we ran two experiments. First (E1), commercial hybrid hens were reared either in aviary or barren brooding cages, then housed in aviary, conventional cages or furnished (enriched) cages, thus forming different maternal housing treatments. Hens from each treatment were inseminated at three ages, and measures of egg composition, yolk testosterone concentration and offspring’s development, anxiety and fearfulness were assessed. In experiment 2 (E2), maternal age effects on offspring's growth and behaviour were further investigated using fertile eggs from commercial breeder flocks at three different ages. Results from E1 showed that Old hens laid heavier eggs with less yolk testosterone and produced offspring with fewer indicators of anxiety and fearfulness. Maternal rearing and housing affected egg traits, offspring weight and behaviour, but not in a consistent way. Effects of maternal age were not replicated in E2, possibly due to differences in management or higher tolerance to maternal effects in commercial breeders. Overall, our research confirms that maternal age and maternal environment affects egg composition, with maternal age specifically affecting yolk testosterone concentration, which may mediate physical and behavioural effects in offspring.

Maternal P2X7 receptor inhibition prevents autism-like phenotype in male mouse offspring through the NLRP3-IL-1β pathway

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition caused by interactions of environmental and genetic factors. Recently we showed that activation of the purinergic P2X7 receptors is necessary and sufficient to convert maternal immune activation (MIA) to ASD-like features in male offspring mice. Our aim was to further substantiate these findings and identify downstream signaling pathways coupled to P2X7 upon MIA. Maternal treatment with the NLRP3 antagonist MCC950 and a neutralising IL-1β antibody during pregnancy counteracted the development of autistic characteristics in offspring mice. We also explored time-dependent changes of a widespread cytokine and chemokine profile in maternal blood and fetal brain samples of poly(I:C)/saline-treated dams. MIA-induced increases in plasma IL-1β, RANTES, MCP-1, and fetal brain IL-1β, IL-2, IL-6, MCP-1 concentrations are regulated by the P2X7/NLRP3 pathway. Offspring treatment with the selective P2X7 receptor antagonist JNJ47965567 was effective in the prevention of autism-like behavior in mice using a repeated dosing protocol. Our results highlight that in addition to P2X7, NLRP3, as well as inflammatory cytokines, may also be potential biomarkers and therapeutic targets of social deficits and repetitive behaviors observed in autism spectrum disorder.

Perspective: Re-defining "Pheromone" in a Mammalian Context to Encompass Seminal Fluid.

The classical view of “pheromone”—an air-borne chemical signal—is challenged by the camelids in which ovulation is triggered by ß-nerve growth factor carried in seminal plasma, effectively extending the pheromone concept to a new medium. We propose further extension of “pheromone” to include a separate class of seminal fluid molecules that acts on the female reproductive tract to enhance the prospect of pregnancy. These molecules include transforming growth factor-ß, 19-OH prostaglandins, various ligands of Toll-like receptor-4 (TLR4), and cyclic ADP ribose hydrolase (CD38). They modulate the immune response to “foreign” male-derived histocompatibility antigens on both sperm and the conceptus, determine pre-implantation embryo development, and then promote implantation by increasing uterine receptivity to the embryo. The relative abundance of these immunological molecules in seminal plasma determines the strength and quality of the immune tolerance that is generated in the female. This phenomenon has profound implications in reproductive biology because it provides a pathway, independent of the fertilizing sperm, by which paternal factors can influence the likelihood of reproductive success, as well as the phenotype and health status of offspring. Moreover, the female actively participates in this exchange—information in seminal fluid is subject to “cryptic female choice,” a process by which females interrogate the reproductive fitness of prospective mates and invest reproductive resources accordingly. These processes participate in driving the evolution of male accessory glands, ensuring optimal female reproductive investment and maximal progeny fitness. An expanded pheromone concept will avoid a constraint in our understanding of mammalian reproductive biology.

The influence of environmental conditions on sex determination in the blue mussel Mytilus edulis

Abstract The factors affecting sex determination remain largely unknown for most bivalve species. Environmental factors, such as temperature, are known to influence sex determination in some species, and this has been hypothesized for the mussel Mytilus edulis, but not experimentally validated yet. Adult exposure to different environmental conditions during gametogenesis, which occurs seasonally, may also affect offspring phenotype, including sex determination. Intergenerational carryover effects have been reported in bivalves, but the impact of parental exposures on offspring sex determination has not been examined so far. To address these questions, artificial fertilizations were performed on individuals collected in three different years and their embryos were reared at three different temperatures to specifically test if the environment influences offspring sex ratio through effects on parental developing gametes and/or on developing embryos. The analysis of 1938 embryos from 25 crosses revealed a significant effect of both temperature treatments and sampling years on the proportion of females. However, the overall variation is mostly explained by the “temperature treatment × sampling years” interaction. Taken together, our results suggested that interannual environmental variations experienced by the parents (during gametogenesis) and embryo (during development) can influence the sex of the offspring in M. edulis.