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Parenting from before conception
Abstract
At fertilization, the gametes endow the embryo with a genomic blueprint, the integrity of which is affected by the age and
environmental exposures of both parents. Recent studies reveal that parental history and experiences also exert effects through
epigenomic information not contained in the DNA sequence, including variations in sperm and oocyte cytosine methylation and
chromatin patterning, noncoding RNAs, and mitochondria. Transgenerational epigenetic effects interact with conditions at conception
to program the developmental trajectory of the embryo and fetus, ultimately affecting the lifetime health of the child. These
insights compel us to revise generally held notions to accommodate the prospect that biological parenting commences well before
birth, even prior to conception.
... These data indicate that either 20 and/or 40 ng of the dopamine did not have a detrimental effect on the oocyte expansion. Form the reproduction biology point of view, it appears that normal ovulation and subsequent fertilization depend on the cumulus mass expanding to its optimal size [42-43-44] found a correlation between the rate of [45][46], and the degree of expansion is directly connected to the amount of HA synthesis [36]. Research has demonstrated that FSH stimulates the manufacture of HA novo in vitro [47][48]. ...
... The process by which an immature oocyte halted at prophase of the first meiotic division continues meiosis to become competent for regular fertilization following ovulation is known as oocyte maturation [46]. Oocytes are initially stopped during the prophase of meiosis I in nearly every species that was studied. ...
Proteins and other nitrogenous substances such as polyamines, catecholamines, and nitric oxide require amino acids for synthesis. The purpose of this study was to see how adding dopamine to either maturation or fertilization medium affected the developmental competence of immature bovine oocytes. In this study, Ovaries from apparently normal reproductive organs of cattle were collected within 30 minutes from slaughter and evisceration of animals. Cumulus oocyte complexes (COCs) were collected by aspiration of medium sized ovarian follicles (4-8 mm). COCs of acceptable quality were selected, washed and incubated in tissue culture media (TCM) 199 supplemented with 10% heat inactivated fetal calf serum, 5 μg/ ml luteinizing hormone, 0.5 μg/ ml follicle stimulating hormone and 1 μg/ml estradiol-17β for 20:22 hour at 38.5 C • under 5% CO 2 in air with 90% humidity. different concentrations of dopamine (20,40 ng) were used. The results were consistent for both maturation and fertilization and There is non-significant increase in maturation and fertilization.
... Previous prospective studies have reported that poorer diet quality in pregnancy was associated with impaired child cognitive development [2]. Maternal nutritional cues shape the epigenetic modification of fetal genes, with lasting impacts during implantation, affecting placental growth and nutrient transfer [3]. Therefore, maternal nutrition plays a vital role in fetal brain development, which can have significant implications for the child's future health. ...
Purpose
Our aim was to assess the risk of higher insulinemic, inflammatory, and hyperglycemia potential in the diet during pregnancy with child neurodevelopmental delay.
Methods
We enrolled 7,438 pregnant women participating in a prospective cohort study. The food frequency questionnaire was used to evaluate the empirical dietary index for hyperinsulinemia (EDIH), empirical dietary inflammatory pattern (EDIP), glycemic index (GI), and glycemic load (GL) during mid-pregnancy. Child neurodevelopmental assessment was conducted at 6–36 months postpartum using the Denver Developmental Screening Test-II (DDST-II) scale, and the Gesell Developmental Diagnosis Scale (GDDS) was administered to assess children who did not meet the criteria for passing the DDST-II screening.
Results
We documented 540 incident child neurodevelopmental delay cases over 7,438 pregnant women (median follow-up: 2 years). Pregnant women exhibiting the high levels of hyperinsulinemic or proinflammatory components, or GI encountered an elevated risk of child neurodevelopmental delay; HRs (95% CI) comparing highest to lowest dietary index quintiles were EDIH 1.48 (1.07,2.04; P trend = 0.017), EDIP 1.39 (1.05,1.84; P trend = 0.019) and GI 1.36 (1.02,1.81; P trend = 0.038). In sex-stratified analyses, these results remained significant only in boys (P trend = 0.018 for EDIH, P trend = 0.028 for EDIP, P trend = 0.029 for GI). The performance of combined model of EDIH and EDIP for boys is comparable to that of the combined model of EDIH, EDIP, and GI to assess the risk of neurodevelopmental delay (AUC [area under curve] 0.801 vs. AUC 0.830). Both values are higher than the AUC values achieved by models using either set of indicators individually.
Conclusion
Our findings suggest that maternal consumption of diets with high insulinemic, inflammatory, or glycemic index properties may be associated with neurodevelopmental delays in children, particularly in boys. Higher insulinemic and inflammatory potentials in maternal diet may forecast neurodevelopmental delay in boys.
... This finding was similar to those from previous studies in which increasing age was associated with a gradual decline in the intention to have a third child [28]. In older mothers, age might be associated with reduced fertility and a perceived higher risk of pregnancy and neonatal complications [29]. The optimal reproductive age for women is before the age of 35, as confirmed by several studies. ...
Background
Fertility rates have been decreasing both worldwide and in China. Although current policies have been aimed at raising the birth rate in China, their overall effects have been unclear. Therefore, exploration of fertility intention and related influencing factors is crucial.
Methods
This study used a convergent parallel mixed methods combining descriptive and cross-sectional designs with a framework analysis. Convenience sampling was used to select mothers of childbearing age with two children (n = 603), living in Guangdong Province, China. Participants completed an online questionnaire investigating sociodemographic characteristics, as well as determinants and attitudes regarding the third-child fertility intention. Correlation coefficients and multivariate regression analyses were used to present quantitative findings. Eleven interviews were conducted, and a framework analysis method was used for data analysis. The results for the qualitative and quantitative study components were analyzed separately and were subsequently integrated through side-by-side comparison and joint display.
Result
Attitudes toward fertility intention were negative, and the rate of fertility intention was 10.4% in Guangdong Province. In the quantitative component, women’s age, perceived value of having a third child, and attitudes were found to be factors promoting the intention to have a third child, whereas monthly family income, grandparents’ health status, and policy support were found to be factors hindering the intention to have a third child. Four major themes emerged regarding the perceptions and experiences regarding fertility intention in the qualitative component. After integrated analysis, younger age, knowledge regarding policy support, and access to childcare support were found to be factors significantly affecting the intentions of mothers with two children regarding having a third child.
Conclusion
Fertility issues require continued attention. Our findings provide a reference for optimizing existing policies to increase fertility intentions. Providing policy support, such as public childcare support, flexible working hours for mothers, affordable childcare, and greater psychological support, would enable mothers to improve their parenting. In addition, increasing the dissemination of knowledge regarding policies is necessary to improve the level of public understanding and promote fertility intention.
... There is increasing recognition for the importance of lifestyle and nutrition in reproductive health. Poor adherence to dietary guidelines or nutritional recommendations during the preconception period and throughout pregnancy can negatively impact fertility, pregnancy, and birth outcomes, as well as the future health of the offspring [40,41]. This not only holds for macronutrients, but micronutrients as well. ...
Background
The dietary glycemic index (GI) and load (GL) reflect carbohydrate quality and quantity, potentially impacting fertility through modulation of insulin sensitivity and generation of oxidative stress. While fertility is influenced by both women and men, reproductive research often emphasizes maternal factors. We first examined periconception dietary intake in both women and male partners, and subsequent associations of dietary GI and GL with fecundability and subfertility.
Methods
Among 830 women and 651 male partners, participating in a population-based prospective cohort study from preconception onwards, we assessed periconception dietary intake and calculated GI and GL, using a food frequency questionnaire (FFQ) at median 12.4 weeks gestation (95% range 10.9, 18.4). Information on time to pregnancy was obtained through questionnaires, with subfertility defined as a time to pregnancy ≥ 12 months or use of assisted reproductive technology.
Results
In the periconception period, mean energy intake in women was 1870 kcal (SD: 500; 46% carbohydrates, 16% protein, 33% fat; dietary GI 56.2 (SD: 3.5) and GL 141.4 (SD: 67.4)). Mean energy intake in men was 2350 kcal (SD: 591; 43% carbohydrates, 16% protein, 33% fat; dietary GI 56.8 (SD: 3.2) and GL 156.7 (SD: 75.4)). Median time to pregnancy was 4.8 months (IQR: 1.2, 16.4), with 30.6% of 830 women experiencing subfertility. Dietary GI and GL were not associated with fertility outcomes in women. In men, higher dietary GI and GL across the full range were associated with decreased fecundability, after adjusting for socio-demographic and lifestyle factors, as well as dietary GI or GL of female partners [FR: 0.91, 95% CI 0.83, 0.99; FR: 0.90, 95% CI 0.81, 0.99, per SDS increase in dietary GI and GL, respectively]. When assessing the combined influence of dietary GI clinical categories in women and men, both partners adhering to a low GI diet tended to be associated with increased fecundability, but not with subfertility risk.
Conclusions
Suboptimal periconception carbohydrate intake may be negatively associated with male fertility, but not with fertility outcomes in women. Further studies are needed to assess whether a lower GI and GL diet is a feasible lifestyle intervention to improve couples fertility.
... Maternal preconception nutritional status is a major determinant of embryonic development [22]. Between conception and implantation, the embryo is highly sensitive to nutritive, metabolic, and in ammatory substances in the tubal uid, and these change in response to maternal nutritional changes [23]. Our study is similar to existing ndings [24][25][26] that preconception underweight is strongly associated with SGA. ...
Objective: ART and pre-pregnancy BMI are strongly associated with neonatal outcomes, but there are fewer relevant studies. Our objective was to analyze the association between pre-pregnancy body mass index (BMI) and neonatal outcomes in women planning assisted reproductive technology (ART).
Methods: This was a retrospective study that included 994 ART singleton mothers who delivered in hospitals from July 2020 to June 2024. Mothers were categorized into 4 groups based on BMI (kg/m²): underweight (<18.5), normal weight (18.5-23.9, reference), overweight (24.0–27.9), and obesity (≥28.0). Associations between BMI classification and neonatal outcomes were analyzed using univariate and multivariate logistic regression.
Results: Among all mothers, pre-pregnancy underweight increased the adjusted odds ratio (aOR) for small for gestational age (SGA) to 3.97-fold compared to normal-weight mothers; overweight/obesity significantly increased the risk of macrosomia and large for gestational age (LGA), with aORs of 5.047 and 2.935-fold, respectively. In gestational weight gain (GWG) subgroup analyses, when GWG was adequate, pre-pregnancy underweight mothers were more likely to develop SGA than normal-weight mothers (aOR 4.649, 95% CI: 1.316-16.426), and overweight/obese mothers were not associated with adverse neonatal outcomes. When GWG was excessive, pre-pregnancy underweight mothers were 3.986 times more likely to be at risk of developing SGA than normal-weight mothers; pre-pregnancy overweight/obese mothers were 4.466 and 3.010 times more likely to develop macrosomia and LGA, respectively, compared to normal-weight mothers.
Conclusion: Maternal preconception underweight is associated with SGA regardless of whether GWG is adequate or excessive. For pre-pregnancy overweight or obese mothers, maintaining GWG in the target range can reduce the risk of adverse neonatal outcomes; if GWG is excessive, it is associated with macrosomia and LGA.
... In fact, maternal nutrition intervenes in signaling mechanisms, causing epigenetic remodeling of fetal genes and influencing placental development and nutrient transfer [51]. ...
According to the DSM-5, neurodevelopmental disorders represent a group of heterogeneous conditions, with onset during the developmental period, characterized by an alteration of communication and social skills, learning, adaptive behavior, executive functions, and psychomotor skills. These deficits determine an impairment of personal, social, scholastic, or occupational functioning. Neurodevelopmental disorders are characterized by an increased incidence and a multifactorial etiology, including genetic and environmental components. Data largely explain the role of genetic and environmental factors, also through epigenetic modifications such as DNA methylation and miRNA. Despite genetic factors, nutritional factors also play a significant role in the pathophysiology of these disorders, both in the prenatal and postnatal period, underscoring that the control of modifi-able factors could decrease the incidence of neurodevelopmental disorders. The preventive role of nutrition is widely studied as regards many chronic diseases, such as diabetes, hypertension, and cancer, but actually we also know the effects of nutrition on embryonic brain development and the influence of prenatal and preconceptional nutrition in predisposition to various pathologies. These factors are not limited only to a correct caloric intake and a good BMI, but rather to an adequate and balanced intake of macro and micronutrients, the type of diet, and other elements such as exposure to heavy metals. This review represents an analysis of the literature as regards the physiopathological mechanisms by which food influences our state of health, especially in the age of development (from birth to adolescence), through prenatal and preconceptional changes, underlying how controlling these nutritional factors should improve mothers' nutritional state to significantly reduce the risk of neurodevelopmental disorders in offspring. We searched key words such as "maternal nutrition and neurodevelopmental disorders" on Pubmed and Google Scholar, selecting the main reviews and excluding individual cases. Therefore, nutrigenetics and nutrigenomics teach us the importance of personalized nutrition for good health. So future perspectives may include well-established reference values in order to determine the correct nutritional intake of mothers through food and integration.
... Preconception parental and gestational exposures are an emerging area of interest in our efforts to understand the developmental origins of disease and cognitive dysfunction [76,77]. For example, in humans, periconceptional maternal obesity is associated with an increased risk of age-related diseases, including diabetes, metabolic dysfunction, cardiovascular disease, and cancer [78]. ...
... Exposures to chemical, physical, and biological environmental hazards may occur through leisure activities, hobbies, home renovations and in workplaces, including healthcare, personal care services, manufacturing, and agriculture [15]. Environmental and occupational exposures may impair sperm quality, with chemicals, solvents, endocrine disrupters, heavy metals and radiation established to induce DNA damage or epigenetic modifications [13,[16][17][18]. Sperm quality can also be adversely affected by preconception health behaviors including alcohol consumption, use of illicit drugs and marijuana, tobacco use, and poor nutrition practices contributing to obesity [5,13,19,20]. ...
Background
Reproductive health promotion can enable early mitigation of behavioral and environmental risk factors associated with adverse pregnancy outcomes, while optimizing health of women + (all genders that can gestate a fetus) and babies. Although the biological and social influences of partners on pregnancy are well established, it is unknown whether online Canadian government reproductive health promotion also targets men and partners throughout the reproductive lifespan.
Methods
Reproductive health promotion, designed for the general public, was assessed in a multi-jurisdictional sample of Canadian government (federal, provincial/territorial, and municipal) and select non-governmental organization (NGO) websites. For each website, information related to environmental and behavioral influences on reproductive health (preconception, pregnancy, postpartum) was evaluated based on comprehensiveness, audience-specificity, and scientific quality.
Results
Government and NGO websites provided sparse reproductive health promotion for partners which was generally limited to preconception behavior topics with little coverage of environmental hazard topics. For women + , environmental and behavioral influences on reproductive health were well promoted for pregnancy, with content gaps for preconception and postpartum stages.
Conclusion
Although it is well established that partners influence pregnancy outcomes and fetal/infant health, Canadian government website promotion of partner-specific environmental and behavioral risks was limited. Most websites across jurisdictions promoted behavioral influences on pregnancy, however gaps were apparent in the provision of health information related to environmental hazards. As all reproductive stages, including preconception and postpartum, may be susceptible to environmental and behavioral influences, online health promotion should use a sex- and gender-lens to address biological contributions to embryo, fetal and infant development, as well as contributions of partners to the physical and social environments of the home.
... These epigenetic modifications mediated by the seminal microbiota could transmit paternal programming to offspring, thus influencing developmental homeostasis as well as their lifelong health and disease patterns. Considering that the seminal microbiota resides in the same anatomical region as sperm cells, it is reasonable to speculate that its influence on epigenetic alterations in sperm cells, which could ultimately affect offspring health outcomes [235][236][237][238][239]. Hence a potential mechanism through which the seminal microbiota transmits paternal programming effects is by influencing sperm epigenetics and ultimately offspring epigenetics at conception and during early embryonic development. ...
The field of Developmental Origins of Health and Disease has primarily focused on maternal programming of offspring health. However, emerging evidence suggests that paternal factors, including the seminal microbiome, could potentially play important roles in shaping the developmental trajectory and long-term offspring health outcomes. Historically, the microbes present in the semen were regarded as inherently pathogenic agents. However, this dogma has recently been challenged by the discovery of a diverse commensal microbial community within the semen of healthy males. In addition, recent studies suggest that the transmission of semen-associated microbes into the female reproductive tract during mating has potentials to not only influence female fertility and embryo development but could also contribute to paternal programming in the offspring. In this review, we summarize the current knowledge on the seminal microbiota in both humans and animals followed by discussing their potential involvement in paternal programming of offspring health. We also propose and discuss potential mechanisms through which paternal influences are transmitted to offspring via the seminal microbiome. Overall, this review provides insights into the seminal microbiome-based paternal programing, which will expand our understanding of the potential paternal programming mechanisms which are currently focused primarily on the epigenetic modifications, oxidative stresses, and cytokines.
... Yet, pregnant persons who demonstrate a better ability to limit their food intake when pregnant also exhibit lower levels of perceived hunger [18]. Offsprings' health is also influenced by the non-pregnant partner's health behaviors, including eating behaviors [19][20][21][22]. The evidence suggests that, in non-pregnant partners, the consumption of hypercaloric or high-fat diets may be causal in the etiology of obesity development in their offspring [23][24][25][26][27][28]. ...
Through longitudinal analysis from the GLOWING cohort study, we examined the independent and joint relationships between couples’ eating behaviors and gestational weight gain (GWG). Pregnant persons (n = 218) and their non-pregnant partners (n = 157) completed an Eating Inventory. GWG was calculated as gestation weight at 36 weeks minus that at 10 weeks. General linear models were used to examine the relationships between GWG and the pregnant persons, non-pregnant partners, and couples (n = 137; mean of pregnant persons and non-pregnant partners) cognitive restraint (range 0–21), dietary disinhibition (range 0–18), and perceived hunger (range 0–14), with higher scores reflecting poorer eating behaviors. The adjusted models included race/ethnicity, education, income, marital status, and age. The pregnant persons and their non-pregnant partners’ cognitive restraint, dietary disinhibition, and perceived hunger scores were 9.8 ± 4.7, 4.8 ± 3.2, and 4.4 ± 2.5 and 6.6 ± 4.6, 5.4 ± 3.4, and 4.7 ± 3.2, respectively. Higher cognitive restraint scores among the pregnant persons and couples were positively associated with GWG (p ≤ 0.04 for both). Stratified analyses revealed this was significant for the pregnant persons with overweight (p ≤ 0.04). The non-pregnant partners’ eating behaviors alone were not significantly associated with GWG (p ≥ 0.31 for all). The other explored relationships between GWG and the couples’ eating behaviors were insignificant (p ≥ 0.12 for all). Among the pregnant persons and couples, reduced GWG may be achieved with higher levels of restrained eating. Involving non-pregnant partners in programs to optimize GWG may be beneficial.
... A scoping review has reported that maternal inadequate nutrient intake is linked to diminished cerebral volume, abnormal behavior, and neuropsychiatric conditions such as autism spectrum disorder (ASD), attention de cit and hyperactivity disorder (ADHD), and depression, among others (3). Maternal nutritional cues shape the epigenetic modi cation of fetal genes, with lasting impacts during implantation, affecting placental growth and nutrient transfer (4). Therefore, maternal nutrition plays a vital role in fetal brain development, which can have signi cant implications for the child's future health (5, 6). ...
Background
Insulin response, inflammation, and hyperglycemia are important factors contributing to impaired neural development. However, the relationship between higher insulinemic, inflammatory, and hyperglycemia potential in the diet during pregnancy, and delayed neurodevelopment in children remains unclear. This study explored whether maternal dietary patterns promoting hyperinsulinemia, inflammation, or hyperglycemia may influence child neurodevelopmental delay risk.
Methods
We calculated dietary scores from initial food frequency questionnaires completed by 7,438 pregnant women participating in the Maternal and Infant Health Cohort Study in Hefei (MIH-Hefei). The food frequency questionnaire (FFQ) was used to evaluate the empirical dietary index for hyperinsulinemia (EDIH), empirical dietary inflammatory pattern (EDIP), glycemic index (GI), and glycemic load (GL) during mid-pregnancy. Child developmental assessment was conducted at 6–36 months postpartum.
Results
We documented 540 incident child neurodevelopmental delay cases over 7,438 pregnant women. Pregnant women exhibiting the high levels of hyperinsulinemic or proinflammatory components, or GI encountered an elevated risk of child neurodevelopmental delay; the hazard ratios (HRs) with 95% confidence intervals (CIs) for comparing the highest and lowest dietary indices quintiles were as follows: EDIH 1.48(1.07,2.04; P trend = 0.017), EDIP 1.39(1.05,1.84; P trend = 0.019) and GI 1.36(1.02,1.81; P trend = 0.038). In sex-stratified analyses, these results remained significant only in boys. The performance of combined model of EDIH and EDIP for boys is comparable to that of the combined model of EDIH, EDIP, and GI to assess the risk of neurodevelopmental delay (AUC 0.801 vs. AUC 0.830). Both values are higher than the AUC values achieved by models using either set of indictors individually.
Conclusion
In this prospective cohort study, the maternal consumption of high insulinemic potential diet, high inflammatory potential diet, or high glycemic index diet is related to child neurodevelopmental delay, particularly amongst boys. Higher insulinemic and inflammatory potentials within the maternal diet could potentially forecast child neurodevelopmental delay among boys.
... 5 16-18 Several recent randomised controlled trials (RCTs) and reviews conclude that prepregnancy lifestyle interventions are urgently needed to improve maternal health and increase the likelihood of adherence to a healthy lifestyle during pregnancy. [19][20][21][22][23] Alternative diet-exercise strategies, such as time-restricted eating (TRE) and high-intensity interval training (HIIT), have shown promising results on improving metabolic health among reproductive-aged females. [24][25][26] TRE is a safe and feasible intervention in individuals with overweight, obesity, pre-diabetes and type 2 diabetes. ...
Introduction Gestational diabetes mellitus (GDM) is associated with increased risk for type 2 diabetes in the mother and cardiometabolic diseases in the child. The preconception period is an optimal window to adapt the lifestyle for improved outcomes for both mother and child. Our aim is to determine the effect of a lifestyle intervention, initiated before and continued throughout pregnancy, on maternal glucose tolerance and other maternal and infant cardiometabolic outcomes.
Methods and analysis This ongoing randomised controlled trial has included 167 females aged 18–39 years old at increased risk for GDM who are contemplating pregnancy. The participants were randomly allocated 1:1 to an intervention or control group. The intervention consists of exercise (volume is set by a heart rate-based app and corresponds to ≥ 1 hour of weekly exercise at ≥ 80% of individual heart rate maximum), and time-restricted eating (≤ 10 hours/day window of energy intake). The primary outcome measure is glucose tolerance in gestational week 28. Maternal and offspring outcomes are measured before and during pregnancy, at delivery, and at 6–8 weeks post partum. Primary and secondary continuous outcome measures will be compared between groups based on the ‘intention to treat’ principle using linear mixed models.
Ethics and dissemination The Regional Committees for Medical and Health Research Ethics in Norway has approved the study (REK 143756). The anonymised results will be submitted for publication and posted in a publicly accessible database of clinical study results.
Trial registration number Clinical trial gov NCT04585581.
... As a result, the scope of reproductive health has been broadened to become a synthesis of somatic and germline health. This finds an example in the expression that 'parenting starts before conception' (Lane et al., 2014), referring to the fact that the embryo quality also depends in part on the cues sent by the soma to the maturing gametes. ...
... The foundation for lifelong health for future generations is already established in the parents' reproductive cells before conception (Lane et al., 2014;Patton et al., 2018). The preconception period has three proposed definitions . ...
Improving diet and dietary behaviour of men and women before pregnancy has the potential to benefit both their current and long-term health and the health of their children. Little is known, however, about adults' perception of diet's role in prepregnancy health. This study aimed to explore the state of knowledge and awareness of preconception nutritional health in adults within the fertile age range and what they perceived could motivate healthy eating using the self-determination theory as a theoretical framework. We analysed 33 short exploratory interviews with men (n = 18) and women (n = 15) aged 18-45 years. Participants were grab sampled from three different public locations in the southern part of Norway. Interviews were audio-recorded, transcribed verbatim in 2020 and analysed using a thematic analysis with a semantic approach in 2022. The findings suggest that adults within the fertile age range are not intrinsically motivated to eat healthily, but when they do, it is because eating healthily often aligns with other goals consistent with their values, that is, getting fit or looking good. They possess some basic knowledge of healthy behaviours during pregnancy but are generally unaware of the importance of preconception health and nutrition. There is a need to increase awareness of the impact of preconception health on the health of this and future generations. Improved nutritional education on the significance of diet before conception might facilitate optimal conditions for conceiving and for pregnancy in the adult population within fertile age range.
... Research suggests that the modified extracellular vesicle composition in infertile males also increases the issue of whether and how the primary variables of male infertility, including as age, weight of body, way of life, and environmental exposures, affect the cargo of the extracellular vesicles [49,50]. These exposures have been demonstrated to cause transgenerational changes with considerable effects on offspring health in addition to effects on reproductive status [51][52][53][54][55][56]. ...
The epididymis is responsible for post-testicular sperm maturation as it provides a favorable environment for spermatozoa to gain the ability for movement and fertilization. The recent evidence has shown that, the spermatozoa are vulnerable to dynamic variations driven by various cellular exposure mechanisms mediated by epididymosomes. Exosomes provide new insight into a mechanism of intercellular communication because they provide direct evidence for the transfer of several important bio-active cargo elements (proteins, lipid, DNA, mRNA, microRNA, circular RNA, long noncoding RNA) between epididymis and spermatozoa. In broad sense, proteomic analysis of exosomes from epididymis indicates number of proteins that are involved in sperm motility, acrosomal reaction, prevent pre-mature sperm capacitation and male infertility. Pinpointing, how reproductive disorders are associated with bio-active cargo elements of nano-scale exosome in the male reproductive tract. Therefore, the current review presents evidence regarding the distinctive characteristics and functions of nano-scale exosome in the male reproductive tract in both pathological and physiological developments, and argue that these vesicles serve as an important regulator of male reproduction, fertility, and disease susceptibility.
... Multiple pieces of evidence indicate that sperms contribute their RNA molecules to the oocyte during fertilization (Lane et al., 2014;Sendler et al., 2013;Stoeckius et al., 2014;Yuan et al., 2016). A study from the Rajewsky group used metabolic labeling to show that 10% of the total RNAs have a paternal origin in the fertilized C. elegans early embryos (Stoeckius et al., 2014). ...
Sperm contributes essential paternal factors, including the paternal genome, centrosome, and oocyte-activation signals, to sexual reproduction. However, it remains unresolved how sperm contributes its RNA molecules to regulate early embryonic development. Here, we show that the Caenorhabditis elegans paternal protein SPE-11 assembles into granules during meiotic divisions of spermatogenesis and later matures into a perinuclear structure where sperm RNAs localize. We reconstitute an SPE-11 liquid-phase scaffold in vitro and find that SPE-11 condensates incorporate the nematode RNA, which, in turn, promotes SPE-11 phase separation. Loss of SPE-11 does not affect sperm motility or fertilization but causes pleiotropic development defects in early embryos, and spe-11 mutant males reduce mRNA levels of genes crucial for an oocyte-to-embryo transition or embryonic development. These results reveal that SPE-11 undergoes phase separation and associates with sperm RNAs that are delivered to oocytes during fertilization, providing insights into how a paternal protein regulates early embryonic development.
... Extensive DNA strand repair and chromatin remodeling are involved in spermatogenesis, with histones being largely replaced by protamine, although not completely. Compared to protamine-binding regions, genes in histone-binding regions appear to be more susceptible to DNA damage from smoking, obesity, and aging due to the lack of sperm's ability to repair DNA damage due to oxidative stress [27]. Some supplementations and exercise have been shown to improve sperm function, sperm DNA damage, and the percentage of sperm with persisted histones in animal models [28,29], although these factors were not included in the present study. ...
Purpose:
Male infertility is partially caused by an inappropriate lifestyle and comorbidities. In this study, we analyzed the prevalence of these factors and the effects of lifestyle modifications as part of male preconception care.
Methods:
Four hundred and two male partners of couples seeking conception with abnormal parameters upon the first semen analysis were enrolled. They were advised to modify their inappropriate lifestyle as male preconception care. Afterward, their general and male reproductive health was examined. Semen quality was compared before and after the promotion.
Results:
Smoking, chronic alcohol use, and genital heat stress were found in 22.6%, 47.0%, and 75.1% of patients, respectively. Palpable varicoceles, hypogonadism, obesity (body mass index ≧30 kg/m2), hypertension, zinc deficiency, hyperlipidemia, liver dysfunction, and diabetes mellitus were found in 25.9%, 17.0%, 7.0%, 14.9%, 16.2%, 37.0%, 26.9% and 3.4% of the participants, respectively; 98.8% of the patients had at least one factor. After the promotion, semen parameters and sperm DNA fragmentation were improved significantly. Improvement was found in those with palpable varicocele or hypogonadism but not in those with night work shift, abstinence (>3 days), erectile dysfunction, hypertension, obesity, zinc deficiency, or diabetes mellitus.
Conclusions:
Comorbidities and inappropriate lifestyle choices were common among men with infertility. The promotion of lifestyle modifications as part of male preconception care could improve semen quality without urologic intervention.
... This begins with the early embryo which displays a particular vulnerability to environmental changes possibly leading to modifications in the embryonic development (10). Within the conceptional period, multiple modifications are implemented in the epigenome which increase the susceptibility for dysregulation (6,36). Based on that, ART might represent a perturbance in the fetal environment leading to epigenetic and cardiovascular alterations. ...
Background
Over the past decades, assisted reproductive technologies (ART) have gained remarkable influence in the treatment of infertility and account for more than 2 % of births in European countries nowadays. Accumulating evidence suggests ART to cause cardiovascular alterations, including left ventricular (LV) dysfunctions, within its offspring. The aim of this study was to assess LV systolic function in subjects conceived through ART in comparison to spontaneously conceived peers.Methods
For the assessment of LV morphology and LV function, M-Mode echocardiography, pulsed wave Doppler and two-dimensional speckle tracking echocardiography (2DSTE) were applied. LV ejection fraction (EF) and fractional shortening (FS) were assessed in M-Mode and calculated by Teichholz formula. EF was additionally assessed semiautomatically through 2DSTE.ResultsIn total, 64 ART subjects and 83 spontaneously conceived controls with no significant differences in age (12.52 ± 5.64 years vs. 13.20 ± 5.95 years, p = 0.486) and sex were included in the analysis. In the ART cohort, significantly lower values were observed for M-Mode assessed EF (63.63 ± 5.17 % vs. 65.35 ± 5.10 %, p = 0.046) and FS (34.26 ± 3.87 % vs. 35.60 ± 3.84 %, p = 0.038). However, after the adjustment for birth weight percentile and gestational age, M-Mode assessed EF and FS displayed no significant differences between both groups. LV morphology and remaining systolic function parameters, such as mitral annular plane systolic excursion, aortic velocity time integral, global peak longitudinal strain and 2DSTE measured EF, were comparable between both groups.Conclusion
This study suggests a lower LV systolic function in ART subjects, visualized by significantly lower values for M-Mode assessed EF and FS, compared to spontaneously conceived peers. The clinical relevance of these findings has to be investigated as the above-mentioned parameters were in normal reference range. In addition, LV systolic function parameters evaluated by other echocardiographic imaging modalities were comparable between both groups. Therefore, further studies will be required to evaluate the influence of ART on LV systolic function and cardiovascular morbidity in the future.
... In addition to affecting adult health, parental exposure to a wide range of environmental toxicants including plastic-associated EDCs can cause metabolic disorders, including obesity and diabetes, and these metabolic disease risks can be transmitted to their offspring (Heindel and Blumberg, 2019;Lee and Blumberg, 2019;Sales et al., 2017). Studies from worm to mammal suggest environmental stress-induced phenotypes can be "memorized" in the germline and transmitted to future generations (Daxinger and Whitelaw, 2012;Heard and Martienssen, 2014;Lane et al., 2014;Ost et al., 2014). Most data are obtained from the impact of maternal exposure on the offspring health. ...
Exposure to ubiquitous plastic-associated endocrine disrupting chemicals (EDCs) is associated with the increased risk of many chronic diseases. For example, phthalate exposure is associated with cardiometabolic mortality in humans, with societal costs ∼ $39 billion/year or more. We recently demonstrated that several widely used plastic-associated EDCs increase cardiometabolic disease in appropriate mouse models. In addition to affecting adult health, parental exposure to EDCs has also been shown to cause metabolic disorders, including obesity and diabetes, in the offspring. While most studies have focused on the impact of maternal EDC exposure on the offspring’s health, little is known about the effects of paternal EDC exposure. In the current study, we investigated the adverse impact of paternal exposure to a ubiquitous but understudied phthalate, dicyclohexyl phthalate (DCHP) on the metabolic health of F1 and F2 offspring in mice. Paternal DCHP exposure led to exacerbated insulin resistance and impaired insulin signaling in F1 offspring without affecting diet-induced obesity. We previously showed that sperm small non-coding RNAs including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs) contribute to the intergenerational transmission of paternally acquired metabolic disorders. Using a novel PANDORA-seq, we revealed that DCHP exposure can lead to sperm tsRNA/rsRNA landscape changes that were undetected by traditional RNA-seq, which may contribute to DCHP-elicited adverse effects. Lastly, we found that paternal DCHP can also cause sex-specific transgenerational adverse effects in F2 offspring and elicited glucose intolerance in female F2 descendants. Our results suggest that exposure to endocrine disrupting phthalates may have intergenerational and transgenerational adverse effects on the metabolic health of their offspring. These findings increase our understanding of the etiology of chronic human diseases originating from chemical-elicited intergenerational and transgenerational effects.
... The origin of adult chronic non-communicable diseases across the cardiometabolic and neurological spectrum can arise from the prenatal environment according to the Developmental Origins of Health and Disease (DOHaD) hypothesis [1]. In particular, the period around conception is vulnerable to diverse stress conditions including sub-optimal parental nutrition and assisted reproductive treatments (ART) [2][3][4]. Adverse peri-conceptional environment can alter multiple molecular, cellular and physiological processes in the developmental programme that persist through gestation affecting growth, metabolism and later disease risk, across mammalian species, including humans [2,5,6]. Whilst challenging environmental conditions can evoke developmental plasticity to aid survival, altered programming can become maladaptive where conditions later change leading to pathophysiology [1,2,4]. ...
Peri-conceptional environment can induce permanent changes in embryo phenotype which alter development and associate with later disease susceptibility. Thus, mouse maternal low protein diet (LPD) fed exclusively during preimplantation is sufficient to lead to cardiovascular, metabolic and neurological dysfunction in adult offspring. Embryonic stem cell (ESC) lines were generated from LPD and control NPD C57BL/6 blastocysts and characterised by transcriptomics, metabolomics, bioinformatics and molecular/cellular studies to assess early potential mechanisms in dietary environmental programming. Previously, we showed these lines retain cellular and epigenetic characteristics of LPD and NPD embryos after several passages. Here, three main changes were identified in LPD ESC lines. First, their derivation capacity was reduced but pluripotency marker expression was similar to controls. Second, LPD lines had impaired Mitogen-activated protein kinase (MAPK) pathway with altered gene expression of several regulators (e.g., Maff , Rassf1 , JunD ), reduced ERK1/2 signalling capacity and poorer cell survival characteristics which may contribute to reduced derivation. Third, LPD lines had impaired glucose metabolism comprising reduced upstream enzyme expression (e.g., Gpi, Mpi ) and accumulation of metabolites (e.g., glucose-6-P, fructose-6-P) above the phosphofructokinase (PFK) gateway with PFK enzyme activity reduced. ESC lines may therefore permit investigation of peri-conceptional programming mechanisms with reduced need for animal experimentation.
Graphical Abstract
... A large number of studies have shown that, considering women's physical and mental health, the best childbearing age for women is before the age of 35 [33]. This is because women bear the main responsibility for pregnancy and birth, while older women are more likely to experience infertility and pregnancy complications [34,35]. Thus, with the increase of age, women are more likely to choose not to have a second child. ...
In recent years, an increasing number of women participate in population mobility and most of them are of childbearing age. With the continuous expansion of the population size of this group, their fertility intention will have a great impact on the development of China’s population. Therefore, the aim of this study was to evaluate the fertility intention and influencing factors on having a second child in floating women. This study employed the data from the 2018 National Migrants Dynamic Monitoring Survey data. A self-designed questionnaire was used to collect information, such as socio-demographics and fertility intention. Descriptive statistical analysis was carried out to obtain the basic characteristics of the main variables. Chi-square and ANOVA tests were used to analyze the differences in the basic characteristics between three groups of women (with intention, without intention and unsure about having a second child). Multinomial logistic regression was employed to analyze influencing factors associated with fertility intention among the floating women. The results of this study indicated that only 13.07% of the floating women had the intention to have a second child, while 67.73% had no intention of having another child. In the multivariate analysis, age, gender and age of the first child, reproductive health education, employment status and medical insurance were found to be significant influencing factors of fertility intention (p < 0.05), while education level and household registration type were not associated with the desire to have a second child (p > 0.05). Overall, after the implementation of the universal two-child policy, floating women of childbearing age have reduced intention to have a second child. Reproductive health education and medical insurance play an important role in ensuring the fertility of floating women. This reminds government departments to consider the above factors comprehensively when formulating the next work plan.
... Periconceptually, the epigenome undergoes multiple changes, potentially leading to increased susceptibility to dysregulations [10,41]. The manipulation of the embryo during ART procedures might perturb epigenetic processes, causing alterations in gene expressions [7]. ...
Subjects conceived through assisted reproductive technologies (ART) potentially suffer
from impaired left ventricular (LV) function due to premature vascular aging. This study aimed to
evaluate whether subtle differences in LV diastolic function can be observed echocardiographically
between young ART subjects and their spontaneously conceived peers. The echocardiographic
assessment included the measurement of LV dimensions, mitral inflow velocities, and myocardial
velocity at early diastole (E’, cm/s) at the LV wall and the interventricular septum (IVS). An average
from E/E’LV and E/E’IVS (E/E’AVG) was derived. In total, 66 ART subjects and 83 controls
(12.85 ± 5.80 years vs. 13.25 ± 5.89 years, p = 0.677) were included. The ART subjects demonstrated
a significantly lower E’LV (19.29 ± 3.29 cm/s vs. 20.67 ± 3.78 cm/s, p = 0.020) compared to their
spontaneously conceived peers. Study participants of ≥ 10 years of age displayed a significantly
higher E/E’AVG (6.50 ± 0.97 vs. 6.05 ± 0.99, p = 0.035) within the ART cohort. The results of this
study demonstrate a significantly lower LV diastolic function in the ART subjects. However, no
significant changes in LV diastolic function were observed between the two groups when the results
were adjusted for age, birth weight percentile, and gestational age. Those ART subjects born preterm
might have an elevated risk of developing LV diastolic alterations and could therefore profit from
close echocardiographic monitoring.
... Factors influencing parental health and well-being before conception (preconception), including nutrition, lifestyle habits, and medication, can influence both gametogenesis and embryogenesis and the subsequent long-term health and development of offspring (Fleming et al., 2018;Lane et al., 2014;Steegers-Theunissen et al., 2013). Increased incidence of morbidity and mortality demonstrates that health and well-being during the preconception period is particularly important for people with preexisting chronic physical and mental health conditions (Jack et al., 2008;Knight et al., 2021;Persson et al., 2009). ...
Preconception care for people with chronic health conditions is recommended in view of the implications for them and their offspring during pregnancy and beyond. This realist review of published and grey literature explored factors that explain why people seek or receive appropriate preconception counseling and why they engage in recommended health behavior change prior to pregnancy. Fifty-two studies contributed to phase one synthesis, and 38 studies provided explanations in phase two. Ten program theories were developed, explored, and refined through iterative discussion and coding. Causal explanations of the ways in which components of preconception care contribute to effective access to care and prepregnancy behavior change were identified. Beneficial components included continuity of carer (promoting trust), a partnership approach (empowering people who feel valued), promoting an integrated approach across primary and secondary care, offering psychological counseling (recognizing the link between physical and psychosocial aspects of living with health conditions), considering sexual and reproductive health as part of routine care, and normalizing conversations about preconception care (to reduce the barrier created by social and cultural norms). These key aspects have been highlighted for consideration when planning, implementing, and improving preconception care services for people with health conditions.
... Furthermore, studies in many taxa have explicitly shown that the composition of seminal fluid (i.e., the absolute and relative amounts of proteins, peptides, etc. in the seminal fluid) responds highly plastically to different environmental factors [35][36][37][38][39][40][41][42][43][44] and is also subject to the interaction between genotypes and environments [45,46]. Therefore, seminal fluid protein, peptide and nucleic acid content (hereafter referred to as Sfc for short) may play a more significant role in epigenetic inheritance and the transmission of environmentally-induced paternal effects to the next generations than has hitherto been suspected [6,[47][48][49][50][51][52]. ...
The evidence supports the occurrence of environmentally-induced paternal epigenetic inheritance that shapes the offspring phenotype in the absence of direct or indirect paternal care and clearly demonstrates that sperm epigenetics is one of the major actors mediating these paternal effects. However, in most animals, while sperm makes up only a small portion of the seminal fluid, males also have a complex mixture of proteins, peptides, different types of small noncoding RNAs, and cell-free DNA fragments in their ejaculate. These seminal fluid contents (Sfcs) are in close contact with the reproductive cells, tissues, organs, and other molecules of both males and females during reproduction. Moreover, their production and use are adjusted in response to environmental conditions, making them potential markers of environmentally- and developmentally-induced paternal effects on the next generation(s). Although there is some intriguing evidence for Sfc-mediated paternal effects, the underlying molecular mechanisms remain poorly defined. In this review, the current evidence regarding the links between seminal fluid and environmental paternal effects and the potential pathways and mechanisms that seminal fluid may follow in mediating paternal epigenetic inheritance are discussed.
... Subsequently, during transit through the epididymis, additional epigenetic signals are conferred to sperm as they mature to become fertilization competent, including alterations in noncoding RNAs and additional changes in posttranslational histone modifications (Yoshida et al., 2018;Bedi et al., 2022a;Conine and Rando, 2022) (Figure 1). Over the past 10 years, clinical and biomedical studies have demonstrated that epigenetic factors carried in sperm significantly influence the health of future generations (Lane et al., 2014;Fleming et al., 2018). These studies have challenged the exclusive importance of gestational exposures in mediating environmentally-induced disease and provide compelling evidence to help redress the notion that exposure-induced birth defects are solely the woman's fault. ...
Our efforts to understand the developmental origins of birth defects and disease have primarily focused on maternal exposures and intrauterine stressors. Recently, research into non-genomic mechanisms of inheritance has led to the recognition that epigenetic factors carried in sperm also significantly impact the health of future generations. However, although researchers have described a range of potential epigenetic signals transmitted through sperm, we have yet to obtain a mechanistic understanding of how these paternally-inherited factors influence offspring development and modify life-long health. In this endeavor, the emerging influence of the paternal epigenetic program on placental development, patterning, and function may help explain how a diverse range of male exposures induce comparable intergenerational effects on offspring health. During pregnancy, the placenta serves as the dynamic interface between mother and fetus, regulating nutrient, oxygen, and waste exchange and coordinating fetal growth and maturation. Studies examining intrauterine maternal stressors routinely describe alterations in placental growth, histological organization, and glycogen content, which correlate with well-described influences on infant health and adult onset of disease. Significantly, the emergence of similar phenotypes in models examining preconception male exposures indicates that paternal stressors transmit an epigenetic memory to their offspring that also negatively impacts placental function. Like maternal models, paternally programmed placental dysfunction exerts life-long consequences on offspring health, particularly metabolic function. Here, focusing primarily on rodent models, we review the literature and discuss the influences of preconception male health and exposure history on placental growth and patterning. We emphasize the emergence of common placental phenotypes shared between models examining preconception male and intrauterine stressors but note that the direction of change frequently differs between maternal and paternal exposures. We posit that alterations in placental growth, histological organization, and glycogen content broadly serve as reliable markers of altered paternal developmental programming, predicting the emergence of structural and metabolic defects in the offspring. Finally, we suggest the existence of an unrecognized developmental axis between the male germline and the extraembryonic lineages that may have evolved to enhance fetal adaptation.
Attention‐Deficit Hyperactive Disorder (ADHD) is a neurobehavioral syndrome affecting children aged 6–17 with symptoms manifesting before age 12. ADHD presents heterogeneously and is associated with various psychiatric disorders. The cause remains elusive, but genetic and environmental factors, brain region maturation delays, and neurotransmitter dysregulation are implicated. Effective treatment requires a multi‐disciplinary approach, primarily involving pharmacological and behavioral intervention. Stimulants like methylphenidate and amphetamines are first‐line medications, but non‐stimulants may be considered for some patients. However, stimulants face challenges related to misuse, dependence, and long‐term tolerability issues. The etiology of ADHD involved genetic predisposition, environmental influences, and prenatal, perinatal, and postnatal factors. Prenatal causes encompass maternal diet, alcohol consumption, viral infections, and stress. Postnatal factors include head trauma, meningitis, toxin, nutritional deficiencies, as well as iodine deficiency and hypothyroidism. The gut microbiome's role in ADHD is emerging, influencing neurodevelopment through microbiota–gut–brain axis. Understanding these diverse etiological factors is essential for comprehensive ADHD management.
The purpose of the present study was to find out the effect of hatha yoga sadhana and simplified kundalini yoga on selected physiological variable among geriatric men with low back ache. The study was conducted on 45 Geriatric men with low back ache Totally three groups, namely, control & experimental group I & II, consisting or 15 Geriatric men with low back ache underwent six weeks practice in Hatha yoga sadhana and simplified kundalini yoga whereas the control group did not under go any type of training. The pulse rate was measured before and after the experimentation using the standard equipment ( Citizen) . The data were analyzed by Analysis of Co-variance (ANCOVA) and it was concluded that the Hatha yoga sadhana and simplified kundalini yoga had significant (P < 0.05) effect on the Pulse rate level.
Environmental variation often induces plastic responses in organisms that can trigger changes in subsequent generations through non-genetic inheritance mechanisms. Such transgenerational plasticity thus consists of environmentally induced non-random phenotypic modifications that are transmitted through generations. Transgenerational effects may vary according to the sex of the organism experiencing the environmental perturbation, the sex of their descendants or both, but whether they are affected by past sexual selection is unknown. Here, we use experimental evolution on an insect model system to conduct a first test of the involvement of sexual selection history in shaping transgenerational plasticity in the face of rapid environmental change (exposure to pesticide). We manipulated evolutionary history in terms of the intensity of sexual selection for over 80 generations before exposing individuals to the toxicant. We found that sexual selection history constrained adaptation under rapid environmental change. We also detected inter- and transgenerational effects of pesticide exposure in the form of increased fitness and longevity. These cross-generational influences of toxicants were sex dependent (they affected only male descendants), and intergenerational, but not transgenerational, plasticity was modulated by sexual selection history. Our results highlight the complexity of intra-, inter- and transgenerational influences of past selection and environmental stress on phenotypic expression.
The "One Health" idea comprises a global strategy emphasizing the need for an approach that is whole and transdisciplinary and integrates multisector expertise in dealing with the health of man, animals, and the environment. It stimulates and promotes the interconnectedness, coexistence, and evolution of living things and their environment, which is itself in a state of constant evolution. Industrialization, geopolitical problems, and an increase in human population have led to increasing global changes causing a lot of damage to biodiversity, extensive deterioration of ecosystems, and considerable migratory movement of both mankind and species in general. Over the years, certain zoonoses, such as bird flu or the Ebola and Zika viral epidemics, have illustrated this fact to the entire world demonstrating the interdependence of human health, animal health, and ecosystem health. Many of the same microbes infect animals and humans, as they share the ecosystems, they live in. Efforts by just one sector cannot prevent or eliminate the problem. One toxicology combines wildlife, human, veterinary, and ecological toxicology to support more logical choices as to what chemicals and what concentrations are permitted to come into contact with human beings and their domestic animals. Ecosystems serve as a life support system to mankind. Humans take great advantage of the resources provided by the planet and by doing so the environment is being modified. The shared environment and food sources of animals and humans allow potential exposure to the same toxic and infectious agents. In this review article, we discuss the connection between toxicology, ecosystem health, and one health.
Background
The use of selective serotonin reuptake inhibitors (SSRIs) has increased over time. Several studies indicate that paternal use of medication may adversely affect the developing fetus. Only a few studies have investigated the association between preconceptional paternal exposure to SSRIs and the risks of adverse health outcomes in children.
Objectives
This study aimed to assess adverse birth outcomes and adverse early life events in children fathered by men using SSRIs prior to conception.
Materials and methods
All live‐born singleton children born in Denmark from 1997 until 2019 and their parents were included. The exposed cohort comprised all children fathered by men using SSRIs 3 months prior to conception and the unexposed cohort comprised all other children. We estimated the odds ratios for adverse birth outcomes: small for gestational age (SGA), preterm birth, low Apgar score, and major congenital malformations. Furthermore, we estimated the hazard ratios for adverse early life events of infections and hospitalizations within 1 year from birth. We also examined adverse birth outcomes and the adverse early life events according to SSRI subgroups.
Results
There was a statistically significantly increased odds ratio 1.15 (confidence interval, CI: 1.06–1.23) for preterm birth. No significant results were found for SGA, low Apgar score, and major congenital malformations. The adjusted hazard ratios for hospitalizations and infections were 1.06 (CI: 1.02–1.11) and 1.02 (CI: 0.97–1.07), respectively. There was a statistically significantly increased odds ratio for preterm birth with respect to the SSRI subgroups citalopram and escitalopram, and for hospitalizations with respect to citalopram.
Discussion and conclusion
Although the risks of certain adverse birth and adverse early life outcomes were statistically significantly increased, the ratios were small and may have limited clinical importance. Paternal use of SSRI was in general safe in the preconceptual period.
Mammalian preimplantation embryos often contain chromosomal defects that arose in the first divisions after fertilization and affect a subpopulation of cells - an event known as mosaic aneuploidy. In this issue of the JCI, Chavli et al. report single-cell genomic sequencing data for rigorous evaluation of the incidence and degree of mosaic aneuploidy in healthy human in vitro fertilization (IVF) embryos. Remarkably, mosaic aneuploidy occurred in at least 80% of human blastocyst-stage embryos, with often less than 20% of cells showing defects. These findings confirm that mosaic aneuploidy is prevalent in human embryos, indicating that the process is a widespread event that rarely has clinical consequences. There are major implications for preimplantation genetic testing of aneuploidy (PGT-A), a test commonly used to screen and select IVF embryos for transfer. The application and benefit of this technology is controversial, and the findings provide more cause for caution on its use.
This chapter reviews the impact of stigma on infants of adolescent parents. Stigma based on misinformation about teen parents is pervasive and contributes directly to the burden of difficulties in the lives of teen parents and their children. It is a form of toxic stress that fosters a dysfunctional stress management system in infancy, leading to compromised health and development in all domains. It impacts parents and their children with adverse outcomes over the lifespan. Some interventions show promise but require further study.
Background and aim
Paternal use of analgesics during the time of conception and adverse birth outcomes are poorly studied. We investigated the association between paternal exposure to non‐steroid anti‐inflammatory drugs and opioids within 3 months before the date of conception and the risk of adverse birth outcomes (preterm birth, small for gestational age, low Apgar score, and major congenital malformations).
Methods
We used nationwide data from the Danish health registers. We included information on all singleton live births, and their fathers and mothers from 1997 to 2018. We created two exposed cohorts, children with preconception paternal exposure to (1) non‐steroid anti‐inflammatory drugs and (2) opioids. The unexposed cohort was children without preconception paternal exposure to non‐steroid anti‐inflammatory drugs or opioids, and we performed a sub‐analysis against paternal use of acetaminophen (paracetamol). We used logistic regression models to estimate the odds ratios of adverse birth outcomes including 95% confidence intervals.
Results
We identified 1,260,934 children, 45,667 children with paternal exposure to non‐steroid anti‐inflammatory drugs, 10,086 children with paternal exposure to opioids, and 1,205,181 unexposed children. The adjusted odds ratio for preterm birth was 1.08 (95% confidence interval, 1.03–1.13) after paternal exposure to non‐steroid anti‐inflammatory drugs and 1.21 (95% confidence interval, 1.08–1.35) after paternal exposure to opioids. The adjusted odds ratio for small for gestational age was 1.09 (95% confidence interval, 1.03–1.17) after paternal exposure to non‐steroid anti‐inflammatory drugs, and 1.03 (95% confidence interval, 0.88–1.21) after paternal exposure to opioids. We found null‐associations for a low Apgar score and major congenital malformations. Estimates were attenuated when compared against paternal paracetamol exposure.
Conclusions
Overall, we found null‐associations across the comparisons made. Weak associations were found for paternal exposure to non‐steroid anti‐inflammatory drugs or opioids and preterm birth and small for gestational age, but not with low Apgar score or major congenital malformation. All associations were attenuated when compared against an active comparator of paternal paracetamol exposure. The effect sizes were small and less likely to be of clinical relevance.
Seminal plasma (SP) accounts for more than 90% of semen volume. It induces inflammation, regulates immune tolerance, and facilitates embryonic development and implantation in the female reproductive tract. In the physiological state, SP promotes endometrial decidualization and causes changes in immune cells such as macrophages, natural killer cells, regulatory T cells, and dendritic cells. This leads to the secretion of cytokines and chemokines and also results in the alteration of miRNA profiles and the expression of genes related to endometrial tolerance and angiogenesis. Together, these changes modulate the endometrial immune microenvironment and contribute to implantation and pregnancy. However, in pathological situations, abnormal alterations in SP due to advanced age or poor diet in men can interfere with a woman's immune adaptation to pregnancy, negatively affecting embryo implantation and even the health of the offspring. Uterine pathologies such as endometriosis and endometritis can cause the endometrium to respond negatively to SP, which can further contribute to pathological progress and interfere with conception. The research on the mechanism of SP in the endometrium is conducive to the development of new targets for intervention to improve reproductive outcomes and may also provide new ideas for semen-assisted treatment of clinical infertility.
Until recently, clinicians and researchers did not realize paternal exposures could impact child developmental outcomes. Indeed, although there is growing recognition that sperm carry a large amount of non-genomic information and that paternal stressors influence the health of the next generation, toxicologists are only now beginning to explore the role paternal exposures have in dysgenesis and the incidence of congenital malformations. In this commentary, I will briefly summarize the few studies describing congenital malformations resulting from preconception paternal stressors, argue for the theoretical expansion of teratogenic perspectives into the male preconception period, and discuss some of the challenges in this newly emerging branch of toxicology. I argue that we must consider gametes the same as any other malleable precursor cell type and recognize that environmentally-induced epigenetic changes acquired during the formation of the sperm and oocyte hold equal teratogenic potential as exposures during early development. Here, I propose the term epiteratogen to reference agents acting outside of pregnancy that, through epigenetic mechanisms, induce congenital malformations. Understanding the interactions between the environment, the essential epigenetic processes intrinsic to spermatogenesis, and their cumulative influences on embryo patterning is essential to addressing a significant blind spot in the field of developmental toxicology.
Background:
Risk factors for problematic child eating behaviours and food preferences are thought to begin during the preconception period. It is unknown if maternal preconception BMI is associated with child nutritional risk factors (e.g., poor dietary intake and eating behaviours).
Objectives:
To determine whether maternal preconception BMI was associated with child nutritional risk.
Design:
In this longitudinal cohort study, a secondary data analysis of children ages 18 months to 5 years were recruited from The Applied Research Group for Kids (TARGet Kids!), a primary care practice-based research network in Canada. The primary exposure was maternal preconception BMI. The primary outcome was parent-reported child nutritional risk score, measured using the NutriSTEP®, an age-appropriate validated questionnaire. Fitted linear mixed effects models analyzed associations between maternal preconception BMI and child nutritional risk after adjusting for covariates.
Results:
This study included 4733 children with 8611 repeated NutriSTEP® observations obtained between ages 18 months to 5 years. The mean (SD) maternal preconception BMI was 23.6 (4.4), where 73.1% of mothers had a BMI <24.9kg/m2, and 26.9% had a BMI > 25kg/m2. The mean (SD) NutriSTEP® total score was 13.5 (6.2), with 86.6% at low risk (score <21) and 13.4% at high risk (score >21). Each 1 unit increase in maternal preconception BMI was associated with a 0.09 increase in NutriSTEP® total score (95% CI 0.05, 0.12, p= <0.001). After stratification, each 1 unit increase in maternal BMI was associated with a 0.06 increase in mean NutriSTEP® total score (95% CI 0.007, 0.11, p=0.025) in toddlers, and 0.11 increase in mean NutriSTEP® total score (95% CI 0.07, 0.15, p<0.001) in preschoolers.
Conclusion:
This work found higher maternal preconception BMI was associated with slightly higher NutriSTEP® total scores. This provides evidence that the preconception period may be an important time to focus on for improving childhood nutrition.
Clinical trial registry:
Clinicaltrials.gov, registered under NCT01869530.
Aims:
Evidence is accumulating that maternal inflammation induces phenotypic changes in the next generation. However, whether maternal preconceptional inflammation alters metabolic and behavioral phenotypes in offspring remains poorly understood.
Main methods:
Female mice were injected with either lipopolysaccharide or saline to establish the inflammatory model and then allowed to mate with normal males. Offspring from both control and inflammatory dams were subsequently given chow diet and water ad libitum, without any challenge, for metabolic and behavioral tests.
Key findings:
Male offspring derived from inflammatory mothers (Inf-F1) maintained on the chow diet developed impaired glucose tolerance and hepatic ectopic fat deposition. Hepatic transcriptome sequencing showed the largest gene changes related to the metabolic pathway. Moreover, Inf-F1 mice exhibited anxiety- and depressive-like behaviors and were accompanied by higher serum corticosterone concentration and lower glucocorticoid receptor abundance in the hippocampus.
Significance:
The results expand the current knowledge of developmental programming of health and disease to include maternal preconceptional health and provide a basis for understanding metabolic and behavioral alterations in offspring linked to maternal inflammation.
At present allergic diseases are detected in 30% people and their frequency is only growing. A significant role in allergic pathology occurrence belongs to ambient air contamination and chemicals being introduced not only into children’s bodies, but their parents’ ones as well since pollutants can act as allergens and sensitizing agents. Our research goal was to examine influence exerted by parents’ pre-gestation exposure to chemicals on sensitization among teenagers living in an area where ambient air was contaminated. We examined overall immunoglobulin E contents and leukocytes migration inhibition test with formaldehyde and sodium nitrite in 115 teenagers whose parents worked under adverse working conditions at chemical and petrochemical enterprises and in 244 schoolchildren whose parents didn’t have any occupational contacts with chemicals. Each group was divided into sub-groups depending on inhalation chemical burden on schoolchildren’s bodies caused by ambient air contamination and contaminated air indoors (with hazard index (HI) for immune disorders being lower than 2 and HI≥2). The research allowed establishing that teenagers whose parents had worked at chemical and petrochemical enterprises during a pre-gestation period had elevated IgE contents more frequently as well as changes in leukocytes migration inhibition test with formaldehyde; it indicated there was sensitization to this chemical. Parents’ occupational contacts with chemicals led to an increase in relative risks of elevated igE contents and 2.5 times higher sensitization among schoolchildren with HI<2. Risk that sensitization to formaldehyde might occur was equal to 2.3 among senior schoolchildren with HI≥2 whose parents worked at chemical enterprises.
The concept of the early life developmental origins of health and disease (DOHaD) in adults has stimulated a new approach to understanding disease trajectories, with major public health implications. Indeed, the principle of the 'lifecourse of disease' now influences health policies internationally. Environmental influences during pregnancy and early life that affect lifelong health are well documented, but there is a new focus on the preconception period and the significance of paternal health on the fetus. This fully revised second edition highlights scientific and clinical advances in the field, exploring new understanding of mechanisms such as epigenetics and the increasingly recognised role of external influences, including pollution. The book is structured logically, covering environment, clinical outcomes, mechanisms of DOHaD, interventions throughout the lifespan and finally implications for public health and policy. Clinicians and scientists alike will improve their understanding of the developmental origins of health and disease with this essential text.
Increasingly, couples struggling with fertility turn to assisted reproductive techniques, including in vitro fertilization (IVF), to have children. Despite the demonstrated influence of periconception male health and lifestyle choices on offspring development, studies examining IVF success rates and child health outcomes remain exclusively focused on maternal factors. Using a physiologically relevant mouse model, we tested the hypothesis that chronic paternal preconception alcohol intake adversely affects IVF success and negatively impacts IVF offspring fetoplacental growth. Using a voluntary, binge-like mouse model, we exposed sexually mature C57BL/6J males to three preconception treatments (0% (Control), 6% EtOH or 10% EtOH) for six weeks, isolated and cryopreserved caudal sperm from treated males, and then used these samples to fertilise oocytes before assessing IVF embryo developmental outcomes. We found that preconception paternal alcohol use reduced IVF embryo survival and pregnancy success rates in a dose-dependent manner, with the pregnancy success rate of the 10% EtOH treatment falling to half those of the Controls. Mechanistically, we found that preconception paternal alcohol exposure disrupts embryonic gene expression, including Fgf4 and Egfr, two critical regulators of trophectoderm stem cell growth and placental patterning, with lasting impacts on the histological organization of the late-term placenta. The changes in placental histoarchitecture were accompanied by altered regulation of pathways controlling mitochondrial function, oxidative phosphorylation and some imprinted genes. Our studies indicate that male alcohol use may significantly impede IVF success rates, increasing the couple's financial burden and emotional stress, and highlights the need to expand prepregnancy messaging to emphasize the reproductive dangers of alcohol use by both parents.
Maternal obesity can impair offspring metabolic health, however the precise mechanism underpinning programming is unknown. Ten-Eleven translocase (TET) enzymes demethylate DNA using the TCA cycle intermediary α-ketoglutarate and may be involved in programming offspring health. Whether TETs are disrupted by maternal obesity is unknown.
5-6 week old C57Bl/6 female mice were fed a control diet (CD; 6% fat, n=175) or a high-fat diet (HFD; 21% fat, n=158) for six weeks. After superovulation oocytes were collected for metabolic assessment, or females were mated and zygotes cultured for embryo development, foetal growth, and assessment of global DNA methylation (5mC, 5hmC, 5fC and 5caC) in the 2-cell embryo. Zygotes collected from superovulated CBAF1 females were cultured in media containing α-ketoglutarate (0mM, 1.4mM, 3.5mM, or 14.0mM) or with 2-hydroxyglutarate (2HG) (0mM or 20mM), a competitive inhibitor of α-ketoglutarate, with methylation and blastocyst differentiation assessed.
After HFD, oocytes showed increased pyruvate oxidation and intracellular ROS, with no changes in Tet3 expression, while 2-cell embryo global 5hmC DNA methylation was reduced and 5fC increased. Embryos cultured with 1.4 mM α-ketoglutarate had decreased 2-cell 5mC, whilst 14.0mM α-ketoglutarate increased the 5hmC:5mC ratio. In contrast supplementation with 20 mM 2HG increased 5mC and decreased the 5fC:5mC and 5caC:5mC ratios. α-ketoglutarate up to 3.5mM did not alter embryo development, whilst culturing in 14.0mM α-ketoglutarate blocked development at the 2-cell. Culture with 2HG delayed embryo development past the 4-cell and decreased blastocyst total cell number.
In conclusion, disruptions in metabolic intermediates in the preimplantation embryo may provide a link between maternal obesity and programming offspring for ill health.
Embryo culture during assisted reproduction treatment may be associated with altered risks for health and aging across the lifespan of the offspring.
With the development of nanotechnology, nanomaterials offer great advantages in a wide variety of industrial and consumer products, and show promise for biomedical applications. However, with these new products, nanomaterial pollutants may enter the human body to cause adverse health effects, including hazards to the male reproductive system. Nanomaterials can enter the body through inhalation, oral exposure, or intravenous injection, and reach the testis via the blood, penetrate the Sertoli cell barrier, and directly or indirectly elicit toxicopathological changes to the testicles. These may then trigger hormone disorders, inhibit spermatogenic cell proliferation, and induce apoptosis, ultimately leading to a decrease in sperm motility and number, ultimately diminishing male reproductive capacity. This review will discuss the toxicological effects of nanomaterials on the male reproductive system, including inflammation, the impact on the hypothalamic–pituitary–gonadal axis (HPG axis), lipid peroxidation, and free ion release relevant to germ cells, Sertoli cell tight junctions, and the gonadal endocrine system. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Nanomaterials may cause hazards to male reproductive system, such as the hormone disorders and a decrease in sperm motility and number.
Gives an overview of the role of semen analysis and spern function testing in the assessment of the reproductive system in adrology and in the aetiology of male factor infertility. Considers the convergence of semen anaysis reference methodology and the vital importance of training in achieving competency and controlling measurement uncertainty. Discusses how the andrology laboratory provides test results that help direct patient management, and the importance of safe and effective sperm preparation as part of assisted conception treatments.
Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological
data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming
model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining
regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ
cell development can impact the male germline methylome, associated with metabolic disease in offspring.
BACKGROUND Increasing numbers of children are being conceived by assisted reproductive technology (ART). A number of studies have highlighted
an altered epigenetic status in gametes from infertile couples and the possibility of an increased risk of imprinting defects
and somatic epigenetic changes in ART conceived children, but the results have been heterogeneous. We performed a systematic
review of existing studies to compare the incidence of imprinting disorders and levels of DNA methylation in key imprinted
genes in children conceived through in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with those in children conceived spontaneously.
In experimental animals, maternal diet during the periconceptional period influences the establishment of DNA methylation at metastable epialleles in the offspring, with permanent phenotypic consequences. Pronounced naturally occurring seasonal differences in the diet of rural Gambian women allowed us to test this in humans. We show that significant seasonal variations in methyl-donor nutrient intake of mothers around the time of conception influence 13 relevant plasma biomarkers. The level of several of these maternal biomarkers predicts increased/decreased methylation at metastable epialleles in DNA extracted from lymphocytes and hair follicles in infants postnatally. Our results demonstrate that maternal nutritional status during early pregnancy causes persistent and systemic epigenetic changes at human metastable epialleles.
In-vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus naturally, under energy balanced and high-fat overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80mU/m(2)/min), was lower in IVF (n=14) versus controls (n=20) after 3 days of an energy-balanced diet (30% fat). In response to 3-days of overfeeding (+1250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P=0.02). Mice conceived following either ovarian stimulation alone or IVF weighed significantly less at birth versus controls (P<0.01). However, only mice conceived by IVF displayed increased fasting glucose, impaired glucose tolerance and reduced insulin-stimulated Akt phosphorylation in liver following 8 weeks of either chow or high-fat diet (60% fat). Thus, ovarian stimulation impaired fetal growth in mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of developing metabolic diseases later in life, and in both mouse and humans.
Small non-coding RNAs (sncRNAs) are potential vectors at the interface between genes and environment. We found that traumatic stress in early life altered mouse microRNA (miRNA) expression, and behavioral and metabolic responses in the progeny. Injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring.
The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases like diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertility, disturbs homeostasis and affects long-term growth and metabolism. To address this controversy, we have assessed the effects of in vitro fertilization (IVF) on postnatal physiology in mice. We demonstrate that IVF and embryo culture, even under conditions considered optimal for mouse embryo culture, alter postnatal growth trajectory, fat accumulation and glucose metabolism in adult mice. Unbiased metabolic profiling in serum and microarray analysis of pancreatic islets and insulin sensitive tissues (liver, skeletal muscle and adipose tissue) revealed broad changes in metabolic homeostasis, characterized by systemic oxidative stress and mitochondrial dysfunction. Adopting a candidate approach, we identify thioredoxin-interacting protein (TXNIP)-a key molecule involved in integrating cellular nutritional and oxidative states with metabolic response-as a marker for preimplantation stress and demonstrate tissue-specific epigenetic and transcriptional TXNIP misregulation in selected adult tissues. Importantly, dysregulation of TXNIP expression was associated with enrichment for H4 acetylation at the Txnip promoter that persisted from the blastocyst stage through adulthood in adipose tissue. Our data supports the vulnerability of preimplantation embryos to environmental disturbance, and demonstrates that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness. This study has wide clinical relevance and underscores the importance of continued follow-up of IVF-conceived offspring.
Zinc is an essential nutrient for optimal fertility, but the effects of preconception zinc deficiency on postimplantation development are not known. Female mice were fed a control or a zinc deficient diet (ZDD) for 4-5 days before ovulation (preconception). Embryonic and/or placental development were evaluated on Days 3.5, 6.5, 10.5, 12.5 and 16.5 of pregnancy. The findings show a decrease in embryo length (31%, Day 10.5; 13%, Day 12.5; 10%, Day 16.5) and weight (23%, Day 16.5) in embryos from mothers fed a ZDD preconception. Zinc deficiency also caused a high incidence of pregnancy loss (46%, Day 10.5; 34%, Day 12.5; 51%, Day 16.5) compared to control (2%, Day 10.5; 7%, Day 12.5; 9%, Day 16.5). ZDD embryos transferred to normal recipients were 38% smaller and implantation rate was only 10% compared to 40% for controls. Trophoblast cell differentiation and implantation on Day 6.5 of pregnancy were compromised by preconception zinc deficiency. On Day 12.5 of pregnancy, placenta weight and area of fetal placenta were decreased 37% and a 31% respectively by preconception zinc deficiency. Consistent with a smaller fetal placenta, expression of key placental transcripts including, Ar, Esx1, Syna, Tfeb, Dlx3 and Gcm1 mRNA, but not Ctsq mRNA were decreased 30-70% in the ZDD group. Preconception zinc deficiency caused 41-57% of embryos to exhibit delayed or aberrant neural tube development as examined by light microscopy and magnetic resonance imaging (MRI). Collectively, the findings provide evidence for the importance of preconception zinc in promoting optimal fertility and oocyte developmental potential.
Mammalian extra-embryonic lineages perform the crucial role of nutrient provision during gestation to support embryonic and fetal growth. These lineages derive from outer trophectoderm (TE) and internal primitive endoderm (PE) in the blastocyst and subsequently give rise to chorio-allantoic and visceral yolk sac placentae, respectively. We have shown maternal low protein diet exclusively during mouse preimplantation development (Emb-LPD) is sufficient to cause a compensatory increase in fetal and perinatal growth that correlates positively with increased adult-onset cardiovascular, metabolic and behavioural disease. Here, to investigate early mechanisms of compensatory nutrient provision, we assessed the influence of maternal Emb-LPD on endocytosis within extra-embryonic lineages using quantitative imaging and expression of markers and proteins involved. Blastocysts collected from Emb-LPD mothers within standard culture medium displayed enhanced TE endocytosis compared with embryos from control mothers with respect to the number and collective volume per cell of vesicles with endocytosed ligand and fluid and lysosomes, plus protein expression of megalin (Lrp2) LDL-family receptor. Endocytosis was also stimulated using similar criteria in the outer PE-like lineage of embryoid bodies formed from embryonic stem cell lines generated from Emb-LPD blastocysts. Using an in vitro model replicating the depleted amino acid (AA) composition found within the Emb-LPD uterine luminal fluid, we show TE endocytosis response is activated through reduced branched-chain AAs (leucine, isoleucine, valine). Moreover, activation appears mediated through RhoA GTPase signalling. Our data indicate early embryos regulate and stabilise endocytosis as a mechanism to compensate for poor maternal nutrient provision.
Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle-related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non-coding RNAs are viable mechanistic candidates for a non-genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health-related effects in future generations.
We previously showed that paternal high-fat diet (HFD) consumption programs β-cell dysfunction in female rat offspring, together with transcriptome alterations in islets. Here we investigated the retroperitoneal white adipose tissue (RpWAT) transcriptome using gene and pathway enrichment and pathway analysis to determine whether commonly affected network topologies exist between these two metabolically related tissues. In RpWAT, 5108 genes were differentially expressed due to a paternal HFD; the top 5 significantly enriched networks identified by pathway analysis in offspring of HFD fathers compared with those of fathers fed control diet were: mitochondrial and cellular response to stress, telomerase signaling, cell death and survival, cell cycle, cellular growth and proliferation, and cancer. A total of 187 adipose olfactory receptor genes were down-regulated. Interrogation against the islet transcriptome identified specific gene networks and pathways, including olfactory receptor genes that were similarly affected in both tissues (411 common genes, P<0.05). In particular, we highlight a common molecular network, cell cycle and cancer, with the same hub gene, Myc, suggesting early onset developmental changes that persist, shared responses to programmed systemic factors, or crosstalk between tissues. Thus, paternal HFD consumption triggers unique gene signatures, consistent with premature aging and chronic degenerative disorders, in both RpWAT and pancreatic islets of daughters.-Ng, S.-F., Lin, R. C., Maloney, C. A., Youngson, N. A., Owens, J. A., Morris, M. J. Paternal high-fat diet consumption induces common changes in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female rat offspring.
One of the major causes of defective sperm function is oxidative stress, which not only disrupts the integrity of sperm DNA but also limits the fertilizing potential of these cells as a result of collateral damage to proteins and lipids in the sperm plasma membrane. The origins of such oxidative stress appear to involve the sperm mitochondria, which have a tendency to generate high levels of superoxide anion as a prelude to entering the intrinsic apoptotic cascade. Unfortunately, these cells have very little capacity to respond to such an attack because they only possess the first enzyme in the base excision repair (BER) pathway, 8-oxoguanine glycosylase 1 (OGG1). The latter successfully creates an abasic site, but the spermatozoa cannot process the oxidative lesion further because they lack the downstream proteins (APE1, XRCC1) needed to complete the repair process. It is the responsibility of the oocyte to continue the BER pathway prior to initiation of S-phase of the first mitotic division. If a mistake is made by the oocyte at this stage of development, a mutation will be created that will be represented in every cell in the body. Such mechanisms may explain the increase in childhood cancers and other diseases observed in the offspring of males who have suffered oxidative stress in their germ line as a consequence of age, environmental or lifestyle factors. The high prevalence of oxidative DNA damage in the spermatozoa of male infertility patients may have implications for the health of children conceivedin vitro and serves as a driver for current research into the origins of free radical generation in the germ line.
Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor (Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.
Children conceived by assisted reproductive technologies (ART) display a level of vascular dysfunction similar to that seen in children of mothers with preeclamspia. The long-term consequences of ART-associated vascular disorders are unknown and difficult to investigate in healthy children. Here, we found that vasculature from mice generated by ART display endothelial dysfunction and increased stiffness, which translated into arterial hypertension in vivo. Progeny of male ART mice also exhibited vascular dysfunction, suggesting underlying epigenetic modifications. ART mice had altered methylation at the promoter of the gene encoding eNOS in the aorta, which correlated with decreased vascular eNOS expression and NO synthesis. Administration of a deacetylase inhibitor to ART mice normalized vascular gene methylation and function and resulted in progeny without vascular dysfunction. The induction of ART-associated vascular and epigenetic alterations appeared to be related to the embryo environment; these alterations were possibly facilitated by the hormonally stimulated ovulation accompanying ART. Finally, ART mice challenged with a high-fat diet had roughly a 25% shorter life span compared with control animals. This study highlights the potential of ART to induce vascular dysfunction and shorten life span and suggests that epigenetic alterations contribute to these problems.
Obesity is highly prevalent, and its incidence is increasing. The previous study showing a major effect of paternal obesity on metabolic health of offspring is confounded by comorbidity with diabetes. Therefore, we investigated the effect of diet-induced paternal obesity, in the absence of diabetes, on the metabolic health of two resultant generations and the molecular profiles of the testes and sperm. Founder (F0) male C57BL6 mice were fed either a high-fat diet (HFD) or a control diet (CD); n = 10/diet for a period of 10 wk. Testis expression of mRNA/microRNAs was analyzed by microarray and qPCR and sperm microRNA abundance by qPCR Two subsequent generations were generated by mating F0 and then F1 mice to CD mice, and their metabolic health was investigated. All mice, other than F0 males, were maintained on a CD. HFD feeding induced paternal obesity with a 21% increase in adiposity, but not overt diabetes, and initiated intergenerational transmission of obesity and insulin resistance in two generations of offspring. This distinct phenotypic constellation is either partially or fully transmitted to both female and male F1 offspring and further transmitted through both parental lineages to the F2 generation, with a heightened effect on female F1 offspring (+67% in adiposity) and their F2 sons (+24% in adiposity). Founder male obesity altered the testes expression of 414 mRNAs by microarray and 11 microRNAs by qPCR, concomitant with alterations in sperm microRNA content and a 25% reduction in global methylation of germ cell DNA Diet-induced paternal obesity modulates sperm microRNA content and germ cell methylation status, which are potential signals that program offspring health and initiate the transmission of obesity and impaired metabolic health to future generations. This study implicates paternal obesity in the transgenerational amplification of obesity and type 2 diabetes in humans.
Background
Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene.
Methods
We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m2.
Results
Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome.
Conclusions
While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.
Background
Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, fetal loss, congenital abnormalities and neonatal conditions. Furthermore, the proportion of reproductive-aged woman that are obese in the population is increasing sharply. From current studies it is not clear if the origin of the reproductive complications is attributable to problems that arise in the oocyte or the uterine environment.
Methodology/Principal Findings
We examined the developmental basis of the reproductive phenotypes in obese animals by employing a high fat diet mouse model of obesity. We analyzed very early embryonic and fetal phenotypes, which can be parsed into three abnormal developmental processes that occur in obese mothers. The first is oocyte meiotic aneuploidy that then leads to early embryonic loss. The second is an abnormal process distinct from meiotic aneuploidy that also leads to early embryonic loss. The third is fetal growth retardation and brain developmental abnormalities, which based on embryo transfer experiments are not due to the obese uterine environment but instead must be from a defect that arises prior to the blastocyst stage.
Conclusions/Significance
Our results suggest that reproductive complications in obese females are, at least in part, from oocyte maternal effects. This conclusion is consistent with IVF studies where the increased pregnancy failure rate in obese women returns to the normal rate if donor oocytes are used instead of autologous oocytes. We postulate that preconceptional weight gain adversely affects pregnancy outcomes and fetal development. In light of our findings, preconceptional counseling may be indicated as the preferable, earlier target for intervention in obese women desiring pregnancy and healthy outcomes.
The aim of this study was to examine paternal age in relation to risk of autism spectrum disorders (ASDs) in a setting other than the industrialized west.
A case-control study of Aruban-born children (1990-2003). Cases (N = 95) were identified at the Child and Adolescent Psychiatry Clinic, the only such clinic in Aruba; gender and age matched controls (N = 347) were gathered from public health records. Parental age was defined categorically (≤29, 30-39, 40-49, ≥50y). The analysis was made, using conditional logistic regression.
Advanced paternal age was associated with increased risk of ASDs in offspring. In comparison to the youngest paternal age group (≤29y), risk of autism increased 2.18 times for children born from fathers in their thirties, 2.71 times for fathers in their forties, and 3.22 thereafter.
This study, part of the first epidemiologic study of autism in the Caribbean, contributes additional evidence, from a distinctive sociocultural setting, of the risk of ASD associated with increased paternal age.
Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 × 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.
MicroRNAs belonging to the miR-34 family have been proposed as critical modulators of the p53 pathway and potential tumor suppressors in human cancers. To formally test these hypotheses, we have generated mice carrying targeted deletion of all three members of this microRNA family. We show that complete inactivation of miR-34 function is compatible with normal development in mice. Surprisingly, p53 function appears to be intact in miR-34-deficient cells and tissues. Although loss of miR-34 expression leads to a slight increase in cellular proliferation in vitro, it does not impair p53-induced cell cycle arrest or apoptosis. Furthermore, in contrast to p53-deficient mice, miR-34-deficient animals do not display increased susceptibility to spontaneous, irradiation-induced, or c-Myc-initiated tumorigenesis. We also show that expression of members of the miR-34 family is particularly high in the testes, lungs, and brains of mice and that it is largely p53-independent in these tissues. These findings indicate that miR-34 plays a redundant function in the p53 pathway and suggest additional p53-independent functions for this family of miRNAs.
Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1-F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease.
Stability and function of eukaryotic genomes are closely linked to chromatin structure and organization. During cell division the entire genome must be accurately replicated and the chromatin landscape reproduced on new DNA. Chromatin and nuclear structure influence where and when DNA replication initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation. Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle. If DNA synthesis is perturbed, cells can suffer loss of both genome and epigenome integrity with severe consequences for the organism.
Maternal periconceptional (PC) nutrition, coupled with maternal physiological condition, can impact on reproductive performance and potential across mammalian species. Oocyte quality and embryo development are affected adversely by either nutrient restriction or excess. Moreover, the quality of maternal PC nutrition can have lasting effects through fetal development and postnatally into adulthood. Chronic disease, notably cardiovascular and metabolic disease, and abnormal behaviour have been identified in adult offspring in small and large animal models of PC nutrient restriction. These long-term effects associate with compensatory responses that begin from the time of early embryo development. This review assesses the field of PC nutrition in vivo on short- and long-term developmental consequences in rodent and ruminant models and considers the implications for human health.
In mammals, the sperm deliver mRNA of unknown function into the oocytes during fertilization. The role of sperm microRNAs (miRNAs) in preimplantation development is unknown. miRNA profiling identified six miRNAs expressed in the sperm and the zygotes but not in the oocytes or preimplantation embryos. Sperm contained both the precursor and the mature form of one of these miRNAs, miR-34c. The absence of an increased level of miR-34c in zygotes derived from α-amanitin-treated oocytes and in parthenogenetic oocytes supported a sperm origin of zygotic miR-34c. Injection of miR-34c inhibitor into zygotes inhibited DNA synthesis and significantly suppressed first cleavage division. A 3' UTR luciferase assay and Western blotting demonstrated that miR-34c regulates B-cell leukemia/lymphoma 2 (Bcl-2) expression in the zygotes. Coinjection of anti-Bcl-2 antibody in zygotes partially reversed but injection of Bcl-2 protein mimicked the effect of miR-34c inhibition. Oocyte activation is essential for the miR-34c action in zygotes, as demonstrated by a decrease in 3'UTR luciferase reporter activity and Bcl-2 expression after injection of precursor miR-34c into parthenogenetic oocytes. Our findings provide evidence that sperm-borne miR-34c is important for the first cell division via modulation of Bcl-2 expression.
Human and animal studies have revealed a strong association between periconceptional environmental factors, such as poor maternal diet, and an increased propensity for cardiovascular and metabolic disease in adult offspring. Previously, we reported cardiovascular and physiological effects of maternal low protein diet (LPD) fed during discrete periods of periconceptional development on 6-month-old mouse offspring. Here, we extend the analysis in 1 year aging offspring, evaluating mechanisms regulating growth and adiposity. Isocaloric LPD (9% casein) or normal protein diet (18% casein; NPD) was fed to female MF-1 mice either exclusively during oocyte maturation (for 3.5 days prior to mating; Egg-LPD, Egg-NPD, respectively), throughout gestation (LPD, NPD) or exclusively during preimplantation development (for 3.5 days post mating; Emb-LPD). LPD and Emb-LPD female offspring were significantly lighter and heavier than NPD females respectively for up to 52 weeks. Egg-LPD, LPD and Emb-LPD offspring displayed significantly elevated systolic blood pressure at 52 weeks compared to respective controls (Egg-NPD, NPD). LPD females had significantly reduced inguinal and retroperitoneal fat pad: body weight ratios compared to NPD females. Expression of the insulin receptor (Insr) and insulin-like growth factor I receptor (Igf1r) in retroperitoneal fat was significantly elevated in Emb-LPD females (P<0.05), whilst Emb-LPD males displayed significantly decreased expression of the mitochondrial uncoupling protein 1 (Ucp1) gene compared to NPD offspring. LPD females displayed significantly increased expression of Ucp1 in interscapular brown adipose tissue when compared to NPD offspring. Our results demonstrate that aging offspring body weight, cardiovascular and adiposity homeostasis can be programmed by maternal periconceptional nutrition. These adverse outcomes further exemplify the criticality of dietary behaviour around the time of conception on long-term offspring health.
Male obesity is associated with reduced sperm function and increased incidence of sperm DNA damage; however, the underlying molecular mechanisms have not yet been identified. Mammalian SIRT6 protein is involved in caloric-dependant DNA damage repair in other tissue types, yet a possible role for SIRT6 in male obesity and subfertility has not been investigated previously. To assess SIRT6 levels and activity in the testes, male mice (n=12 per diet) were fed either a control diet (CD; 6% fat) or a high-fat diet (HFD; 21% fat) for 16 weeks before the collection of testes and spermatozoa. SIRT6 protein was localised to the nucleus of transitional spermatids and the acrosome of mature spermatozoa, with levels significantly decreased in HFD-fed male mice (P<0.05). This decrease in SIRT6 protein was associated with transitional spermatids having increased levels of acetylated H3K9 in the nucleus (P<0.01) and increased DNA damage (P<0.001). We propose a role for SIRT6 in spermiogenesis and potentially protamination processes, which are known to be compromised by male obesity.
Background
The preimplantation embryo is sensitive to culture conditions in vitro and poor maternal diet in vivo . Such environmental perturbations can have long-lasting detrimental consequences for offspring health and physiology. However, early embryo susceptibility to other aspects of maternal health and their potential long-term influence into adulthood is relatively unexplored. In this study, we established an in vivo mouse model of maternal periconceptional systemic inflammation by intraperitoneal lipopolysaccharide (LPS) administration on the day of zygote formation and investigated the consequences into adulthood.
Results
In the short term, maternal LPS challenge induced a transient and typical maternal sickness response (elevated serum proinflammatory cytokines and hypoactive behaviour). Maternal LPS challenge altered preimplantation embryo morphogenesis and cell lineage allocation, resulting in reduced blastocyst inner cell mass (ICM) cell number and a reduced ICM:trophectoderm cell ratio. In the long term, diverse aspects of offspring physiology were affected by maternal LPS treatment. Whilst birthweight, growth and adult blood pressure were unaltered, reduced activity in an open-field behaviour test, increased fat pad:body weight ratio and increased body mass index were observed in male, but not female, offspring. Most importantly, the maternal LPS challenge caused corticosterone-independent blunting of the serum proinflammatory cytokine response to innate immune challenge in both male and female offspring. The suppressed state of innate immunity in challenged offspring was dose-dependent with respect to the maternal LPS concentration administered.
Conclusions
These results demonstrate for the first time that the preimplantation embryo in vivo is sensitive to maternal systemic inflammation, with effects on blastocyst cell lineage allocation and consequences for behaviour, adiposity and innate immune response in adult offspring. Critically, we identify a novel mechanism mediated through maternal-embryonic interactions that confers plasticity in the development of the innate immune system, which is potentially important in setting postnatal tolerance to environmental pathogens. Our study extends the concept of developmental programming of health and disease to include maternal health at the time of conception.
The sperm chromatin of fertile men retains a small number of nucleosomes that are enriched at developmental gene promoters and imprinted gene loci. This unique chromatin packaging at certain gene promoters provides these genomic loci the ability to convey instructive epigenetic information to the zygote, potentially expanding the role and significance of the sperm epigenome in embryogenesis. We hypothesize that changes in chromatin packaging may be associated with poor reproductive outcome.
Seven patients with reproductive dysfunction were recruited: three had unexplained poor embryogenesis during IVF and four were diagnosed with male infertility and previously shown to have altered protamination. Genome-wide analysis of the location of histones and histone modifications was analyzed by isolation and purification of DNA bound to histones and protamines. The histone-bound fraction of DNA was analyzed using high-throughput sequencing, both initially and following chromatin immunoprecipitation. The protamine-bound fraction was hybridized to agilent arrays. DNA methylation was examined using bisulfite sequencing.
Unlike fertile men, five of seven infertile men had non-programmatic (randomly distributed) histone retention genome-wide. Interestingly, in contrast to the total histone pool, the localization of H3 Lysine 4 methylation (H3K4me) or H3 Lysine 27 methylation (H3K27me) was highly similar in the gametes of infertile men compared with fertile men. However, there was a reduction in the amount of H3K4me or H3K27me retained at developmental transcription factors and certain imprinted genes. Finally, the methylation status of candidate developmental promoters and imprinted loci were altered in a subset of the infertile men.
This initial genome-wide analysis of epigenetic markings in the sperm of infertile men demonstrates differences in composition and epigenetic markings compared with fertile men, especially at certain imprinted and developmental loci. Although no single locus displays a complete change in chromatin packaging or DNA modification, the data suggest that moderate changes throughout the genome exist and may have a cumulative detrimental effect on fecundity.
Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01); genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.
Although genetically identical for autosomal Chrs (Chr), male and female preimplantation embryos could display sex-specific transcriptional regulation. To illustrate sex-specific differences at the mRNA level, we compared gene-expression patterns between male and female blastocysts by DNA microarray comparison of nine groups of 60 bovine in vitro-produced blastocysts of each sex. Almost one-third of the transcripts detected showed sexual dimorphism (2,921 transcripts; false-discovery rate, P < 0.05), suggesting that in the absence of hormonal influences, the sex Chrs impose an extensive transcriptional regulation upon autosomal genes. Six genes were analyzed by qPCR in in vivo-derived embryos, which displayed similar sexual dimorphism. Ontology analysis suggested a higher global transcriptional level in females and a more active protein metabolism in males. A gene homolog to an X-linked gene involved in network interactions during spliceosome assembly was found in the Y-Chr. Most of the X-linked-expressed transcripts (88.5%) were up-regulated in females, but most of them (70%) exhibited fold-changes lower than 1.6, suggesting that X-Chr inactivation is partially achieved at the blastocyst stage. Almost half of the transcripts up-regulated in female embryos exhibiting more than 1.6-fold change were present in the X-Chr and eight of them were selected to determine a putative paternal imprinting by gene expression comparison with parthenogenetic embryos. Five (BEX, CAPN6, BEX2, SRPX2, and UBE2A) exhibited a higher expression in females than in parthenotes, suggesting that they are predominantly expressed by the paternal inherited X-Chr and that imprinting may increase the transcriptional skew caused by double X-Chr dosage.
Mammalian mitochondrial DNA (mtDNA) is a small, maternally inherited genome that codes for 13 essential proteins in the respiratory chain. Mature oocytes contain more than 150 000 copies of mtDNA, at least an order of magnitude greater than the number in most somatic cells, but sperm contain only approximately 100 copies. Mitochondrial oxidative phosphorylation has been suggested to be an important determinant of oocyte quality and sperm motility; however, the functional significance of the high mtDNA copy number in oocytes, and of the low copy number in sperm, remains unclear. To investigate the effects of mtDNA copy number on fertility, we genetically manipulated mtDNA copy number in the mouse by deleting one copy of Tfam, an essential component of the mitochondrial nucleoid, at different stages of germline development. We show that males can tolerate at least a threefold reduction in mtDNA copy number in their sperm without impaired fertility, and in fact, they preferentially transmit a deleted Tfam allele. Surprisingly, oocytes with as few as 4000 copies of mtDNA can be fertilized and progress normally through preimplantation development to the blastocyst stage. The mature oocyte, however, has a critical postimplantation developmental threshold of 40 000-50 000 copies of mtDNA in the mature oocyte. These observations suggest that the high mtDNA copy number in the mature oocyte is a genetic device designed to distribute mitochondria and mtDNAs to the cells of the early postimplantation embryo before mitochondrial biogenesis and mtDNA replication resumes, whereas down-regulation of mtDNA copy number is important for normal sperm function.
Significance
Events at conception shape the future growth and health of offspring, to impact life course potential and disease susceptibility. The environment and experiences of both parents contribute to programming offspring phenotype through epigenetic modifications imparted before embryo implantation. How the father transmits this information remains elusive. Possible pathways include the sperm genome and epigenome, postejaculatory effects of seminal fluid on sperm, and indirect actions of seminal fluid on various female factors regulating embryo development. In this study, we provide evidence that seminal fluid acts to influence both sperm integrity and the balance of embryotrophic and embryotoxic signals in the female reproductive tract, in turn affecting embryo development and programming of future adiposity and metabolic phenotype in male offspring.