Reproductive Success In Mammals Research Articles

Ovulation is triggered by a cyclical modulation of gonadotropes into a hyperexcitable state

Gonadotropes in the anterior pituitary gland are essential for fertility and provide a functional link between the brain and the gonads. To trigger ovulation, gonadotrope cells release massive amounts of luteinizing hormone(LH). The mechanism underlying this remains unclear. Here, we utilize a mouse model expressing a genetically encoded Ca2+ indicator exclusively in gonadotropes to dissect this mechanism in intact pituitaries. We demonstrate that female gonadotropes exclusively exhibit a state of hyperexcitability during the LH surge, resulting in spontaneous [Ca2+]i transients in these cells, which persist in the absence of any invivo hormonal signals. L-type Ca2+ channels and transient receptor potential channel A1 (TRPA1) together with intracellular reactive oxygen species (ROS) levels ensure this state of hyperexcitability. Consistent with this, virus-assisted triple knockout of Trpa1 and L-type Ca2+ subunits in gonadotropes leads to vaginal closure in cycling females. Our data provide insight into molecular mechanisms required for ovulation and reproductive success in mammals.

Dorsal raphe serotonin neurotransmission is required for the expression of nursing behavior and for pup survival

Proper maternal care is an essential factor of reproductive success in mammals, involving a repertoire of behaviors oriented toward the feeding and care of the offspring. Among the neurotransmitters involved in the initiation of these behaviors, serotonin (5-HT) seems to play an important role. Here we compared pup-oriented maternal behaviors in mice with constitutive 5-HT depletion, the tryptophan hydroxylase 2-knock-out (Tph2-KO) and the Pet1-KO mice. We report that the only common pup-oriented defect in these 2 hyposerotoninergic models is a defective nursing in parturient mice and altered nursing-like (crouching) behavior in virgin mice, while pup retrieval defects are only present in Tph2-KO. Despite a normal mammary gland development and milk production, the defect in appropriate nursing is responsible for severe growth retardation and early lethality of pups born to hyposerotonergic dams. This nursing defect is due to acute rather constitutive 5-HT depletion, as it is reproduced by adult knockdown of Tph2 in the dorsal raphe nucleus in mothers with a prior normal maternal experience. We conclude that 5-HT innervation from the dorsal raphe is required for both the initiation and maintenance of a normal nursing behavior. Our findings may be related to observations of reduced maternal/infant interactions in human depression.

KH domain containing 3 like (KHDC3L) frame-shift mutation causes both recurrent pregnancy loss and hydatidiform mole

ObjectiveRecurrent pregnancy loss (RPL) is a common infertility-related complication that affects approximately 1–3 % of women worldwide. Known causes of etiology are found in approximately half the cases but the other half remain unexplained. It is estimated that several thousands of genes contribute to reproductive success in mammals and the genetic causes of RPL cannot be fully addressed through targeted genetic tests. In recent years, massive parallel sequencing technologies has helped discovering many causal mutations in hereditary diseases such as RPL. Study designUsing whole-exome sequencing (WES), we studied a large multiplex consanguineous family with multiple cases of RPL and hydatidiform moles (HM). In addition, targeted Sanger sequencing was applied to 40 additional non-related individuals with RPL. ResultsThe use of WES permitted to identify the pathogenic variant in KHDC3L (c.322_325delGACT) in related who experienced RPL with or without HM. Sanger sequencing confirmed the segregation of the mutation throughout the pedigree and permitted to establish this variant as the genetic cause responsible for RPL and HM in this family. ConclusionKHDC3L is well established as a susceptibility gene for HM but we confirmed here that KHDC3L deleterious variants can also induce RPL. In addition, we observed a genotype-phenotype correlation, demonstrating that women with a truncating KHDC3L homozygous variant could not sustain a pregnancy and often had pregnancy losses mainly due to HM while those with the same heterozygous variant could have children but often endured RPL with no HM.

Melatonergic systems of AANAT, melatonin, and its receptor MT2 in the corpus luteum are essential for reproductive success in mammals†

Corpus luteum (CL) plays a critical role in mammalian reproductive physiology. Its dysfunction will lead to infertility or habitual abortion. In the current study, by use of melatonin specific membrane receptor 2 (MT2) knocking out (KO) mice model combined with RNA-Seq, immunohistochemistry, and immunofluorescence analyses, the genes of melatonin synthetic enzyme arylalkylamine N-acetyltransferase (AANAT) and MT2 were identified to strongly express in the CL of sows and mice. KO MT2 significantly impaired the reproductive performance in mice indicated by the reduced litter sizes. Melatonin treatment elevated the progesterone production in sows suggesting the improved CL function. Mechanistic analysis showed that melatonin upregulated a set of progesterone synthesis-related genes including cytochrome P450 family 11 subfamily A member 1 (Cyp11a1), aldo-keto reductase family 1, member C18 (Akr1c18), isopentenyl-diphosphate delta isomerase 1 (Idi1), and luteinizing hormone/choriogonadotropin receptor (Lhcgr). The upregulation of these genes directly related to the increased progesterone production. The regulatory effects of melatonin on these gene expressions were mediated by MT2 and MT2KO diminished the effects of melatonin in this respect. Thus, the presence of melatonergic system of AANAT, melatonin, and its receptor MT2 in CL is essential for reproductive success in mammals.

Monitoring mRNA transcription of genes involved in early pregnancy from endometrium and peripheral blood mononuclear cells of pregnant pigs with different parity.

The reproductive success of mammals is largely dependent on the interaction between maternal and foetal interfaces during early pregnancy. Particularly, immune cells which reside at the maternal endometrium can modulate the conception and placental vascularization. In this study, we analysed the transcription of genes involved in early pregnancy from endometrium and peripheral blood mononuclear cells (PBMCs) of pregnant pigs with different parity. Briefly, three groups of female pigs were divided based on parity (0, 2 and 5) and each group was artificially inseminated. Within 30days of gestation, the total RNA was isolated from the endometrium and PBMCs of sacrificed experimental pigs and the expression patterns of genes involved in early pregnancy were monitored by quantitative real-time RT-PCR. Results indicated absence of correlation between increased parity and the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF-1α) mRNA in endometrium among the groups of pigs analysed. Yet, the mRNA levels of Fas, Fas ligand (FasL) and tumour necrosis factor-α (TNF-α) in the endometrium of parity 5 sows were much higher than those of pregnant gilts (parity 0), and the mRNA ratios of both TNF-α:interleukin-4 (IL-4) and IFN-γ (interferon-γ):interleukin-10 (IL-10) in PBMCs of pregnant pigs were augmented with increasing parity. Furthermore, the mRNA levels of TNF-α and IFN-γ in PBMCs of pregnant pigs were inversely correlated with litter size. These combined results may demonstrate that increased parity of pregnant pigs leads to enhance Th1-prone immunity within the maternal-foetal interface during early pregnancy.

Novel genes and mutations in patients affected by recurrent pregnancy loss.

Recurrent pregnancy loss is a frequently occurring human infertility-related disease affecting ~1% of women. It has been estimated that the cause remains unexplained in >50% cases which strongly suggests that genetic factors may contribute towards the phenotype. Concerning its molecular aetiology numerous studies have had limited success in identifying the disease’s genetic causes. This might have been due to the fact that hundreds of genes are involved in each physiological step necessary for guaranteeing reproductive success in mammals. In such scenario, next generation sequencing provides a potentially interesting tool for research into recurrent pregnancy loss causative mutations.The present study involved whole-exome sequencing and an innovative bioinformatics analysis, for the first time, in 49 unrelated women affected by recurrent pregnancy loss. We identified 27 coding variants (22 genes) potentially related to the phenotype (41% of patients). The affected genes, which were enriched by potentially deleterious sequence variants, belonged to distinct molecular cascades playing key roles in implantation/pregnancy biology.Using a quantum chemical approach method we established that mutations in MMP-10 and FGA proteins led to substantial energetic modifications suggesting an impact on their functions and/or stability.The next generation sequencing and bioinformatics approaches presented here represent an efficient way to find mutations, having potentially moderate/strong functional effects, associated with recurrent pregnancy loss aetiology. We consider that some of these variants (and genes) represent probable future biomarkers for recurrent pregnancy loss.

Incomplete control and concessions explain mating skew in male chimpanzees.

Sexual selection theory predicts that because male reproductive success in mammals is limited by access to females, males will attempt to defend access to mates and exclude rivals from mating. In mammals, dominance rank is correlated with male reproductive success; however, the highest-ranking (alpha) male rarely monopolizes reproduction completely. To explain why, incomplete control models propose that alpha males simply cannot control other males' access to mates. If true, then dominance rank should be a key factor influencing subordinate (non-alpha) male mating success. Alternatively, the concession model states that alpha males can prevent other males from gaining access to mates but posits that they concede matings to subordinates in exchange for social favours. This predicts that a male's grooming interactions with the alpha should mediate his access to females. We test these predictions using 36 years of data, encompassing the tenures of eight alpha male chimpanzees at Gombe National Park, Tanzania. Incomplete control models were most strongly supported. At a given copulation event, the probability that the alpha was the male that mated was negatively associated with the number of males and sexually receptive females in the party. Additionally, as the number of males increased, high dominance rank was associated with an increased likelihood that a particular non-alpha male mated. The concession model, however, was also supported. The amount of time a male spent grooming with the alpha was positively associated with his likelihood of mating when the alpha was present in the party. As grooming is a major affiliative component of male social relationships, our results suggest that social bonds with dominant individuals are leveraged for mating access, particularly in species in which males form coalitions.

HP1BP3 expression determines maternal behavior and offspring survival.

Maternal care is an indispensable behavioral component necessary for survival and reproductive success in mammals, and postpartum maternal behavior is mediated by an incompletely understood complex interplay of signals including effects of epigenetic regulation. We approached this issue using our recently established mice with targeted deletion of heterochromatin protein 1 binding protein 3 (HP1BP3), which we found to be a novel epigenetic repressor with critical roles in postnatal growth. Here, we report a dramatic reduction in the survival of pups born to Hp1bp3(-/-) deficient mouse dams, which could be rescued by co-fostering with wild-type dams. Hp1bp3(-/-) females failed to retrieve both their own pups and foster pups in a pup retrieval test, and showed reduced anxiety-like behavior in the open-field and elevated-plus-maze tests. In contrast, Hp1bp3(-/-) females showed no deficits in behaviors often associated with impaired maternal care, including social behavior, depression, motor coordination and olfactory capability; and maintained unchanged anxiety-associated hallmarks such as cholinergic status and brain miRNA profiles. Collectively, our results suggest a novel role for HP1BP3 in regulating maternal and anxiety-related behavior in mice and call for exploring ways to manipulate this epigenetic process.

Health, growth and reproductive success of mice exposed to environmentally relevant levels of Ra-226 via drinking water over multiple generations

Purpose: To assess health, growth and reproductive success of mammals exposed for multiple generations to levels of radium-226 known to occur in environments surrounding uranium mines and mills in Canada.Methods: The study consisted of a control group and four treatment groups each containing 40 mice (20 males and 20 females) of the CBA/CaJ strain that were continuously exposed to a range of radium-226 levels via drinking water. Breeding was at 8–10 weeks of age and the study was concluded after three breeding cycles.Results: When compared to control mice, constant consumption of drinking water containing 0.012, 0.076, 0.78 and 8.0 Bq/l of radium-226 over four generations of mice did not demonstrably affect physical condition, weight, pregnancy rate, number of pups per litter, sex ratio and bodyweight gain of pups. Between generations, the observed differences in pregnancy rates that were noted in all groups, including controls, seemed to directly correlate with the weight and age of the females at breeding.Conclusions: Based on the endpoints measured on four generations of mice, there is no indication that the consumption of radium-226 via drinking water (at activity concentrations up to 8.0 Bq/l) affects health, growth and reproductive fitness.

Litter sex ratio affects lifetime reproductive success of free‐living female Alpine marmots Marmota marmota†

ABSTRACTIn litter‐bearing mammals, adult phenotype is influenced during prenatal life by the sex of neighbouring foetuses. This phenomenon, found so far only in laboratory studies, may have ecological importance in nature. We present the first evidence that litter sex ratio has consequences for lifetime reproductive success in mammals. Female Alpine marmots born in a male‐biased litter, i.e. more likely to be located in utero next to male foetuses, are more likely to be dominant later in life – a prerequisite for reproduction in this species. We found no evidence for lower reproductive output of these females, a common cost of prenatal masculinization.

Sexual coercion by male chimpanzees shows that female choice may be more apparent than real

The extent to which active female mating preferences influence male reproductive success in mammals is unclear, particularly for promiscuously breeding species like chimpanzees (Pan troglodytes). Previous studies from multiple long-term study sites have shown that female chimpanzees mate more restrictively around ovulation, and this has been taken as evidence for female choice. However, none of these studies rigorously evaluated the alternative hypothesis that restrictive mating results not from unconstrained choice, but in response to coercive mate guarding, in which males use punishment and intimidation to reduce female promiscuity and promote their own mating interests. Nor did they consider evidence for the potential genetic or phenotypic benefits that females might be choosing. Using 11 years of data from the Kanyawara community in Kibale National Park, Uganda, we previously demonstrated that males achieve elevated mating success with those females toward whom they direct high levels of aggression. Here we extend those findings to show that even female copulatory approaches, which have previously been attributed to female choice, are correlated with male aggression. Specifically, individual females at our site initiated periovulatory copulations most frequently with the males who were most aggressive toward them throughout their cycles. Those males showed high rates of aggression toward females throughout estrus, despite achieving high copulation rates, demonstrating a continuing conflict of interest over the exclusivity of mating access. Because sexual coercion is potentially widespread in primates and other mammals, our results stress the importance of considering the influence of male aggression in studies of female choice.

REVIEW ARTICLE: Uterine NK Cells, Spiral Artery Modification and the Regulation of Blood Pressure During Mouse Pregnancy

Reproductive success in mammals involves coordinated changes in the immune and cardiovascular as well as in the neuroendocrine and reproductive systems. This review addresses studies that identify potential links for NK cells and T cells with the local and systemic cardiovascular adaptations of pregnancy. The studies reviewed have utilized immunohistochemisty and in vivo analyses of vascular parameters by ultrasound, chronic monitoring of hemodynamics via radiotelemetric recording and intravital microscopy. At the uterine level, functional subsets of uterine natural killer cells were identified. These included subsets expressing molecules important for vasoregulation, in addition to those previously identified for angiogenesis. Spiral arteries showed conducted responses that could account for conceptus control of vasoactivity and mouse gestational blood pressure 5-phase pattern. Vascular immunology is an emerging transdisciplinary field, critical for both reproductive immunology and cardiovascular disease.

Birth in Free-ranging Macaca fuscata

The birth process is an integral part of reproductive success in mammals, yet detailed, quantitative descriptions of parturition in nonhuman primates are still rare. Observations of free-ranging births can help to elucidate factors involved in this critical event, to contribute to our understanding of how maternal and infant behaviors during parturition affect infant survival and to explain the evolution of human birth. We provide data on the parturition behavior of 4 multiparous Japanese macaques: 2 daytime live births that we photographed and video recorded at the Awajishima Monkey Center (AMC), Awaji Island, Japan in 2006; a daytime live birth video recorded in 1993 at the AMC; and a nocturnal breech stillbirth of a captive Macaca fuscata, video recorded at the Kyoto Primate Research Institute in 2006. Certain behaviors were similar among the females, such as touching of the vulva followed by licking of fingers, squatting during contractions, and average contraction durations. Parturient females facilitated the birth manually by guiding the emerging infant. There were also dissimilarities in the duration of the labor and birth stages, condition of the infant at birth, and the mother’s behavior immediately postpartum. The mother’s postpartum behavior ranged from almost entirely infant-focused to predominantly related to the consumption of the placenta. The 3 free-ranging females all showed considerable social tolerance during labor and birth. We argue that social proximity at parturition is more common in nonhuman primates than previously emphasized, and has potential adaptive advantages.

Repeatability in lactation performance and the consequences for maternal reproductive success in gray seals

In mammals, the most significant maternal effect on offspring growth during lactation is the ability of females to efficiently transfer milk energy to their neonates. However, despite the importance of the transfer of milk energy to both maternal and offspring fitness, nothing is known about the extent to which variation among females may be attributed to differences in individual quality or environmental variation in natural populations. We measured repeatability over multiple lactation periods in components of lactation performance in free-ranging, multiparous gray seal (Halichoerus grypus) females to examine to what extent variation among females in pup weaning mass may be attributed to inherent differences in their physiological capacity to deliver milk energy. Levels of repeatability were high for milk composition (r = 0.38-0.50), daily milk output (r = 0.46), and the duration of lactation (r = 0.57), demonstrating that there are consistent differences among females in these characters across lactations and that the overall capacity of gray seal females to deliver milk energy to their pups is characteristic of individuals. The repeatability in pup weaning mass (r = 0.48) was consistent with the values for the components of total milk energy output and suggests that, over a large proportion of their reproductive life, individual gray seal females will consistently wean pups with greater or lesser probabilities of survival. Our results suggest that inherent differences among females in their physiological capacity to deliver milk energy may be an important component of variation in individual quality and, thus, lifetime reproductive success in mammals. High levels of repeatability also suggest that components of milk energy transfer may have a significant heritable genetic basis.

Wolf Reproduction in Response to Caribou Migration and Industrial Development on the Central Barrens of Mainland Canada

Reproductive success of mammals is greatly influenced by food availability. Where wolves ( Canis lupus ) prey on migratory barren-ground caribou ( Rangifer tarandus ), caribou migration patterns strongly influence food availability for wolves. However, industrial development in formerly undeveloped wolf range could also negatively influence wolf reproduction, either directly (by disrupting normal feeding behavior) or indirectly (by impacting caribou migrations). We used a cross-sectional timeseries regression to analyze eight years of wolf reproductive data with respect to spatial and temporal variation in caribou migration and economic development in a 49 900 km2 area of the Northwest Territories, Canada. Reproductive success decreased as the distance from wolf dens to caribou migration routes increased, while the timing of caribou migrations had little effect. There was no measurable effect of current levels of economic development on reproductive success, although evidence suggests the potential for indirect effects. Continued monitoring is required to identify possible thresholds of adverse effects for wolf populations.

Early experience and parent-of-origin-specific effects influence female reproductive success in mice

Recent studies on mammals investigating parent-of-origin-specific effects such as genomic imprinting and maternal effects have demonstrated their impact on short-term measures of fitness, for example offspring growth. However, the long-term fitness consequences of parent-of-origin-specific effects and their role outside the immediate mother-offspring interaction remain largely unexplored. Here, we show that female mice mated to males that inherited the same set of paternal and maternal genes as themselves have a higher reproductive success than females mated to males of reciprocal genotype. Furthermore, we demonstrate that the early social environment experienced by an individual influences its reproductive success. Females raised with unrelated siblings in a mixed litter had a subsequent lower reproductive success than those that were fostered together with all their biological siblings in unmixed litters. Our results highlight the important influence of parent-of-origin-specific effects and conditions in early development on long-term reproductive success in mammals and suggest that parent-of-origin-specific effects may provide the underlying mechanism for beneficial coadaptation between genotypes, for example, in mate choice.

Factors affecting life and death in Serengeti cheetahs: environment, age, and sociality

We examined environmental and social factors affecting reproductive success across a 20-year data set of individually known cheetahs on the Serengeti Plains of Tanzania. Because cheetahs are seen infrequently and are not amenable to mark–recapture techniques, we devised a model to estimate time of death for individuals that disappeared from our records. We found that males had markedly lower survival than females. Recruitment was negatively affected by rainfall but positively affected by numbers of Thomson’s gazelles, the cheetahs’ chief prey. There was a negative association between recruitment and numbers of lions, demonstrating that the high rates of predation observed in previous studies have implications for the dynamics of cheetah populations. Recruitment was related to mother’s age, peaking when she reached 6–7 years. Sociality affected survival in two ways. First, adolescents living in temporary sibling groups had higher survival than singletons, particularly males with sisters. Second, adult males living in coalitions had higher survival than singletons in periods when other coalitions were numerous, yet they had lower survival when other coalitions were rare. These results corroborate observations of enhanced prey capture by female adolescents and antipredator benefits for adolescents in groups, as well as competitive advantages for adult males in groups. Furthermore, our findings stress the importance of interactions between environmental and social factors in affecting reproductive success in mammals. Key words: Acinonyx jubatus, age, cheetahs, group living, predator avoidance, predator–prey relationships, reproductive success, sociality. [Behav Ecol 15:11–22 (2004)]

Concentrations and dose rate estimates of 134137cesium and 90strontium in small mammals at chornobyl, Ukraine

AbstractFree‐ranging mammals near the Chornobyl nuclear reactor are experiencing substantial radiation dose rates from intramuscular concentrations of 134137Cs and skeletal 90Sr. Radiocesium concentrations averaged 3,200 Bq/g of dry muscle, compared to a mean of 297 Bq 90Sr/g in bone for mammals in the Exclusion Zone, a region of restricted human activity surrounding the reactor. Estimates of dose rates from intramuscular sources of radiocesium averaged 2.4 mGy/d within 8 km of the reactor and ranged as high as 60 mGy/d. Overall dose rates from internal 90Sr for mammals in the Exclusion Zone averaged 1.0 mGy/d, although doses to specific tissues are likely much higher. Mammals captured 30 km southeast of the reactor averaged only 2 Bq/g of muscle and were receiving an average of 1.4 μuGy/d from internal radiocesium. Dramatic variation exists in the spatial pattern of radiocesium in areas immediately surrounding the reactor and within and between remediated and unremediated regions. The variance of 90Sr for taxa among sites was significantly less than that for 134137Cs. Thermoluminescent dosimeters placed on free‐ranging mice showed that dose rates from external sources of radiation were much greater than the dose rates from internal sources of radiocesium. Estimated dose rates in very small areas of the Chornobyl region exceed those reported to impede reproductive success in mammals.

Does reproductive success increase with age or with size in species with indeterminate growth? A case study using sand lizards (Lacerta agilis).

Most data on determinants of reproductive success (RS) and reproductive "tactics" are correlational in nature, and hence cannot be used to infer causation. Consistent patterns-such as an increase in RS with age, as seen in many types of organisms-may result from diverse underlying mechanisms. Ontogenetic increases in RS in mammals and birds may be due largely to direct effects of age (via learning, etc.) but our analyses show that apparently analogous ontogenetic shifts in reproductive tactics and increases in RS in sand lizards (Lacerta agilis) are actually due to ontogenetic changes in body size. When size effects are removed, age exerts very little effect on either reproductive behaviour or RS in either sex. In many taxa, both age and body size may exert important effects on reproductive biology, and disentangling these effects should be a focus of further research.

Spacing behaviour of red squirrels, Sciurus vulgaris: variation between habitats and the sexes

Home range size, range use and range overlap of adult male and female red squirrels in a coniferous and a deciduous woodland were studied using radio-telemetry. Hypotheses, concerning (1) resource predictability and territorial behaviour, and (2) sex-related and habitat-related differences in spacing strategies were tested. In both habitats males had larger home ranges than females. Range size varied seasonally, tending to increase in April–June and to decrease in winter. Both males and females had intensively used core-areas (70% of all locations) that were much smaller than their total range. Dominant males had larger ranges than subordinates, and male body weight was positively correlated with home range size. For females, range size was inversely correlated with food abundance (coniferous area) or local density (deciduous area). Core-area overlap within a sex was smaller than that between sexes. Dominant females defended exlusive core-area overlap within a sex was smaller than that between sexes. Dominant females defended exclusive core-areas against other females, while subordinates behaved as floaters or settled on the edges of the ranges of dominant females. In the deciduous woodland squirrels had larger home ranges, used significantly larger and more strongly overlapping core-areas and were more tolerant of conspecifics than in the coniferous woodland. The results support the hypotheses that (1) the predictability in time and space of food resources, and (2) sexual differences in key resources used to increase reproductive success in mammals with promiscuous or polygynous mating systems, cause differences in spacing behaviour between habitat types and between adult males and females.