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Background: Parental nutritional status is crucial in shaping offspring's kidney development. However, the association between a protein-restrictive diet and its intergenerational impact on kidney development remains unclear. Methods: We conducted multigenerational morphometric measurements to investigate the effects of parental protein deprivation on offspring kidney development across four generations. F0 mice were divided into two groups and fed a normal protein diet (NPD) or a low-protein diet (LPD) for three weeks before mating and continued these diets throughout gestation and lactation. Body weight (BW), kidney weight (KW), KW/BW ratio, nephron counts, and blood pressure were assessed in F1 pups. To examine paternal effects, we bred CD1 females on an NPD with males on an LPD. BW, KW, KW/BW, and nephron counts were measured at P20. To measure the transgenerational effect of parental LPD on kidney development, F1 offspring (from parents on LPD) were fed NPD upon weaning. These F1 offspring were bred at 6 weeks of age to produce F2, F3 and F4 generations. Kidney metrics were evaluated across generations. Results: The average body weight of P0 pups from parents on NPD was 1.61g, while pups from parental LPD weighed an average of 0.869g, a decrease of 54 % (p = 6.9e-11, Wilcoxon test). F1 from parental LPD have significantly smaller kidneys than the control, with an average combined kidney weight of 0.0082g versus 0.0129g, a 37 % decrease (p = 3.2e-02, Wilcoxon test). P20 BW and KW remained low in LPD offspring. These effects persisted for 4 generations (F1 to F4) with an average glomerular count reduction of roughly 20 %. F3 and F4 showed wider variability in glomerular counts but were not statistically significant compared to controls. Conclusions: Both maternal and paternal LPD significantly affected offspring nephron endowment. Our study underscores the complex nature of nutritional transgenerational effects on kidney development, emphasizing the importance of both maternal and paternal dietary impacts on kidney development and the developmental origin of adult disease.

An estimated 250 million children face adverse health outcomes from early life exposure to severe or chronic social, economic, and nutritional adversity, highlighting/emphasizing the pressing concern about the link between ELS and long-term implications on mental and physical health. There is significant overlap between populations experiencing high levels of chronic stress and those experiencing iron deficiency, spotlighting the potential role of iron as a key mediator in this association. Iron, an essential micronutrient for brain development and immune function, is often depleted in stress conditions. Iron deficiency among the most common nutrient deficiencies in the world. Fetal and infant iron status may thus serve as a crucial intermediary between early chronic psychological stress and subsequent immune system changes to impact neurodevelopment. The review presents a hypothesized pathway between early life stress (ELS), iron deficiency, and neurodevelopment through the hypothalamic-pituitary-adrenocortical (HPA) axis and the IL-6-hepcidin axis. This hypothesis is derived from (1) evidence that stress impacts iron status (2) long-term neurodevelopmental outcomes that are shared by ELS and iron deficiency exposure, and (3) possible mechanisms for how iron may mediate the relation between ELS and iron deficiency through alterations in the developing immune system. The article concludes by proposing future research directions, emphasizing the need for rigorous studies to elucidate how stress and iron metabolism interact to modify the developing immune system. Understanding these mechanisms could open new avenues for improving human health and neurodevelopment for women and children globally, making it a timely and vital area of study in psychoneuroimmunology research.

Preterm birth and its related complications have become more and more common as neonatal medicine advances. The concept of “developmental origins of health and disease” has raised awareness of adverse perinatal events in the development of diseases later in life. To explore this concept, we propose that encephalopathy of prematurity (EoP) as a potential pro-inflammatory early life event becomes a novel risk factor for metabolic diseases in children/adolescents and adulthood. Here, we review epidemiological evidence that links preterm birth to metabolic diseases and discuss possible synergic roles of preterm birth and neuroinflammation from EoP in the development of metabolic diseases. In addition, we explore theoretical underlying mechanisms regarding developmental programming of the energy control system and HPA axis.

Objective: We investigated the potential involvement of miRNAs in the developmental programming of cardiovascular diseases (CVD) by maternal obesity. Methods: Serum miRNAs were measured in individuals from the Helsinki Birth Cohort (with known maternal body mass index), and a mouse model was used to determine causative effects of maternal obesity during pregnancy and ischemia-reperfusion on offspring cardiac miRNA expression and release. Results: miR-15b-5p levels were increased in the sera of males born to mothers with higher BMI and in the hearts of adult mice born to obese dams. In an ex-vivo model of perfused mouse hearts, we demonstrated that cardiac tissue releases miR-15b-5p, and that some of the released miR-15b-5p was contained within small extracellular vesicles (EVs). We also demonstrated that release was higher from hearts exposed to maternal obesity following ischaemia/reperfusion. Over-expression of miR-15b-5p in vitro led to loss of outer mitochondrial membrane stability and to repressed fatty acid oxidation in cardiomyocytes. Conclusions: These findings suggest that miR-15-b could play a mechanistic role in the dysregulation of cardiac metabolism following exposure to an in utero obesogenic environment and that its release in cardiac EVs following ischaemic damage may be a novel factor contributing to inter-organ communication between the programmed heart and peripheral tissues.

Background/purpose: Metabolic syndrome (MetS) and overactive bladder might share common pathophysiologies. Environmental fructose exposure during pre- and postnatal periods of rats may program MetS-associated bladder overactivity. We explored the dysregulated insulin signalling at bladder mucosa, as a common mechanism, in facilitating bladder overactivity in rats with MetS induced by maternal and post-weaning fructose diet. Methods: Male offspring of Sprague–Dawley rats were subject into 4 groups by maternal and post-weaning diets (i.e., Control/Control, Fructose/Control, Control/Fructose and Fructose/Fructose by diets). Micturition behavior was evaluated. Acidic ATP solution was used to elicit cystometric reflex along with insulin counteraction. Concentration–response curves to insulin were plotted. The canonical signalling pathway of insulin was evaluated in the bladder mucosal using Western blotting. Levels of detrusor cGMP and urinary NO2 plus NO3 were measured. Results: Male offspring with any fructose exposure presents traits of MetS and bladder overactivity. We observed all fructose exposure groups have the poor urodynamic response to insulin during ATP solution stimulation and poor insulin-activated detrusor relaxation in organ bath study. Compared to controls, the Control/Fructose and Fructose/Fructose groups showed the increased phosphorylation levels of IRS1 (Ser307) and IRS2 (Ser731); thus, suppressed the downstream effectors and urinary NOx/detrusor cGMP levels. The Fructose/Control group showed the compensatory increase of phospho-AKT (Ser473) and phospho-eNOS/eNOS levels, but decreased in eNOS, phospho-eNOS, urinary NOx, and detrusor cGMP levels. Conclusion: Our results show dysregulated insulin signalling at bladder mucosa should be a common mechanism of MetS-associated bladder overactivity programmed by pre-and postnatal fructose diet.

Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases.

Objective: Rodent models raised at environmental temperatures of 21–22 °C are increasingly switched to thermoneutral housing conditions in adulthood to better capture human physiology. We quantified the developmental effects of rearing mice at an ambient temperature of 22 °C vs. 30 °C on metabolic responses to cold and high fat diet (HFD) in adulthood. Methods: Mice were reared from birth to 8 weeks of age at 22 °C or 30 °C, when they were acclimated to single housing at the same temperature for 2–3 weeks in indirect calorimetry cages. Energy expenditure attributable to basal metabolic rate, physical activity, thermic effect of food, and adaptive cold- or diet-induced thermogenesis was calculated. Responses to cooling were evaluated by decreasing the ambient temperature from 22 °C to 14 °C, while responses to HFD feeding were assessed at 30 °C. Influences of rearing temperature on thermogenic responses that emerge over hours, days and weeks were assessed by maintaining mice in the indirect calorimetry cages throughout the study. Results: At an ambient temperature of 22 °C, total energy expenditure (TEE) was 12–16% higher in mice reared at 22 °C as compared to 30 °C. Rearing temperature had no effect on responses in the first hours or week of the 14 °C challenge. Differences emerged in the third week, when TEE increased an additional 10% in mice reared at 22 °C, but mice reared at 30 °C could not sustain this level of cold-induced thermogenesis. Rearing temperature only affected responses to HFD during the first week, due to differences in the timing but not the strength of metabolic adaptations. Conclusion: Rearing at 22 °C does not have a lasting effect on metabolic adaptations to HFD at thermoneutrality, but it programs an enhanced capacity to respond to chronic cold challenges in adulthood. These findings highlight the need to consider rearing temperature when using mice to model cold-induced thermogenesis.

ABSTRACT: In ovo corticosterone (CORT) exposure reportedly reduces growth and alters body composition traits in meat-type chickens. However, the mechanisms governing alterations in growth and body composition remain unclear but could involve myogenic stem cell commitment, and/or the presence of yolk steroid hormones. This study investigated whether in ovo CORT exposure influenced yolk steroid hormone content, as well as embryonic myogenic development in meat-type chickens. Fertile eggs were randomly divided at embryonic day (ED) 11 and administered either a control (CON; 100 µL of 10 mM PBS) or CORT solution (100 µL of 10 mM PBS containing 1 µg CORT) into the chorioallantoic membrane. Yolk samples were collected at ED 0 and ED 5. At ED 15 and hatch, embryos were humanely killed, and yolk and breast muscle (BM) samples were collected. The relative abundance of 15 steroid hormones, along with total lipid content was measured in yolk samples collected at ED 0, ED 5, ED 15, and ED 21. Muscle fiber number, cross-sectional area, and fascicle area occupied by muscle fibers were measured in BM samples collected at hatch. Relative expression of MyoD, MyoG, Pax7, PPARγ, and CEBP/β, and the sex steroid receptors were measured in BM samples collected at hatch. The administration of CORT had a limited effect on yolk steroid hormones. In ovo CORT significantly reduced fascicle area occupied by muscle fibers and CEBP/β expression was increased in CORT exposed birds at hatch. In addition, the quantity of yolk lipid was significantly reduced in CORT-treated birds. In conclusion, in ovo exposure to CORT does not appear to influence early muscle development through yolk steroid hormones in embryonic meat-type chickens however, the results provide a comprehensive analysis of the composition of yolk steroid hormones in ovo at different developmental time points. The findings may suggest increased mesenchymal stem cell commitment to the adipogenic lineage during differentiation and requires further investigation.

Background: Findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial demonstrated a positive effect of gestational cholecalciferol supplementation on offspring bone mineral density (BMD) at age 4 y. Demonstrating the persistence of this effect is important to understanding whether maternal vitamin D supplementation could be a useful public health strategy to improving bone health., Objectives: We investigated whether gestational vitamin D supplementation increases offspring BMD at ages 6-7 y in an exploratory post-hoc analysis of an existing trial., Methods: In the MAVIDOS randomized controlled trial, pregnant females <14 wk' gestation with a singleton pregnancy and serum 25-hydroxyvitamin D 25-100nmol/l at 3 United Kingdom hospitals (Southampton, Sheffield, and Oxford) were randomly assigned to either 1000 IU/d cholecalciferol or placebo from 14 to 17-wk gestation until delivery. Offspring born at term to participants recruited in Southampton were invited to the childhood follow-up at ages 4 and 6-7 y. The children had a dual-energy X-ray absorptiometry (DXA, Hologic discovery) scan of whole-body-less-head (WBLH) and lumbar spine, from which bone area, bone mineral content (BMC), BMD, and bone mineral apparent density (BMAD) were derived. Linear regression was used to compare the 2 groups adjusting for age, sex, height, weight, duration of consumption of human milk, and vitamin D use at 6-7 y., Results: A total of 454 children were followed up at ages 6-7 y, of whom 447 had a usable DXA scan. Gestational cholecalciferol supplementation resulted in higher WBLH BMC [0.15 SD, 95% confidence interval (CI): 0.04, 0.26], BMD (0.18 SD, 95% CI: 0.06, 0.31), BMAD (0.18 SD, 95% CI: 0.04, 0.32), and lean mass (0.09 SD, 95% CI: 0.00, 0.17) compared with placebo. The effect of pregnancy cholecalciferol on bone outcomes was similar at ages 4 and 6-7 y., Conclusions: Supplementation with cholecalciferol 1000 IU/d during pregnancy resulted in greater offspring BMD and lean mass in mid-childhood compared with placebo in this exploratory post-hoc analysis. These findings suggest that pregnancy vitamin D supplementation may be an important population health strategy to improve bone health., Trial Registration Number: This trial was registered at the ISRCTN (https://doi.org/10.1186/ISRCTN82927713) as 82927713 and EUDRACT (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001716-23/results) as 2007-001716-23., Competing Interests: Conflict of interest RJM has received travel bursaries from Kyowa Kirin unrelated to this work. EMC has received travel bursaries or lecture fees from Eli Lilly, Pfizer, Thornton and Ross, and UCB, unrelated to this work. KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, BenevolentAI Bio Ltd., and Danone, outside the submitted work. MKJ reports consultancy and speaker fees from UCB, Amgen, and Kyowa Kirin. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Theramex, Shire, Consilient Healthcare, Kyowa Kirin, and Internis Pharma, outside the submitted work. KAW received Honoraria from Abbott Nutrition unrelated to this work. IS, SRC, and SD declare no conflicts of interest related to the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Level of dam milk production (DMP) and dam milk fat to protein ratio (DFPR), as an indicator of metabolic status in dairy cows, have been identified to be associated with productive and reproductive performance of the offspring. Yet whether the interaction of DMP by DFPR can be associated with performance of the offspring have not been studied to our knowledge. Therefore, the present study was conducted to investigate the association of the main and interactive effects of DMP and DFPR with offspring's birth weight, survival, milk yield and fertility. To this end, data of birth weight, culling rate, milk yield and reproductive variables of offspring born to lactating dams (n = 14,582) and data associated with DMP and DFPR during 305-day lactation were retrieved. Afterwards, offspring were classified in three categories of DMP, including DMP1 (dams with <10.00 × 10 3  kg of 305-day milk production), DMP2 (dams with ≥10.00 × 10 3  kg and <14.00 × 10 3  kg of 305-day milk production), DMP3 (dams with ≥14.00 × 10 3  kg of 305-day milk production), and three categories of DFPR, including DFPR1 (offspring born to dams with <1.00 FPR), DFPR2 (offspring born to dams with ≥1.00 and < 1.40 FPR) and DFPR3 (offspring born to dams with ≥1.40 FPR). Statistical analysis revealed no association of the interaction effect of DMP by DFPR with investigated variables in the offspring (P > 0.05). However, the main effect of DMP was positively associated with milk yield, but negatively associated with survival, age at first insemination and conception during nulliparity, and transgenerational improvement in milk yield in the offspring (P < 0.05). Moreover, the main effect of DFPR was positively associated with birth weight, survival and first service conception rate during nulliparity, but negatively associated with metabolic status and reproductive performance during primiparity in the offspring (P < 0.05). In conclusion, the present study did not find any interaction effect of DMP by DFPR on productive and reproductive variables in the offspring. This finding implicates the association of DMP with milk production in the offspring was regardless of DFPR. Moreover, this finding implies the association of DFPR with postpartum metabolic status and reproductive performance in the offspring was regardless of DMP., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Telomere length (TL) is a biomarker for cellular senescence and TL erosion is predictive of the risk for age-related diseases. Despite being genetically determined at birth, TL may be susceptible to modifications through epigenetic mechanisms. Pollutant agents are considered one of the major threats to both human and planetary health. Their ability to cross the placental barrier and induce oxidative stress in fetal cells is particularly concerning and it may be associated with early TL erosion. In consideration of the timely relevance of this topic, we conducted a literature review on the impact of prenatal exposure to pollutant agents on newborn TL. The search yielded a total of 1099 records, of which only 32 met the inclusion criteria for the review. These criteria included the participation of human subjects, a longitudinal design or collection of longitudinal data, reporting of original TL data, and a focus on exposure to pollutant agents. The majority of the studies reported a significant inverse association between prenatal exposure to pollutant agents and TL. Furthermore, the second trimester of pregnancy emerged as a special sensitive period for the occurrence of pollutant agent-driven TL modifications. Sex differences were inconsistently reported across studies. This review contributes to highlighting biochemical pathways for the threats of environmental pollution to human health. Future research is warranted to further highlight potential buffering mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although the association of maternal milk production with developmental programming of offspring has been investigated, there is limited information available on the relationship of maternal milk components with productive and reproductive performance of the offspring. Therefore, the present study was conducted to analyze the association of maternal milk fat and protein percentage and milk fat to protein ratio with birth weight, survival, productive and reproductive performance and AMH concentration in the offspring. In study I, data of birth weight, milk yield and reproductive variables of offspring born to lactating dams (n = 14,582) and data associated with average maternal milk fat percentage (MFP), protein percentage (MPP) and fat to protein ratio (MFPR) during 305-day lactation were retrieved. Afterwards, offspring were classified in various categories of MFP, MPP and MFPR. In study II, blood samples (n = 339) were collected from offspring in various categories of MFP, MPP and MFPR for measurement of serum AMH. Maternal milk fat percentage was positively associated with birth weight and average percentage of milk fat (APMF) and protein (APMP) and milk fat to protein ratio (FPR) during the first lactation, but negatively associated with culling rate during nulliparity in the offspring (P < 0.05). Maternal milk protein percentage was positively associated with birth weight, APMF, APMP, FPR and culling rate, but negatively associated with milk yield and fertility in the offspring (P < 0.05). Maternal FPR was positively associated with APMF and FPR, but negatively associated with culling rate, APMP and fertility in the offspring (P < 0.05). However, concentration of AMH in the offspring was not associated with MFP, MPP and MFPR (P > 0.05). In conclusion, the present study revealed that maternal milk fat and protein percentage and their ratio were associated with birth weight, survival, production and reproduction of the offspring. Yet it was a preliminary research and further studies are required to elucidate the mechanisms underlying these associations., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although some studies investigated the relationship of dam milk production (DMP) with offspring birth weight and productive performance, limited information is available on the association of level of DMP with reproductive performance in dairy cows. Therefore, the present study was conducted to understand whether dams with various levels of milk production produce offspring with different fertility. In study I, offspring were classified based on the level of DMP into five categories, including DMP1 (dams with <10.00 × 10 3  kg of 305-day milk production), DMP2 (dams with ≥10.00 × 10 3  kg and <12.00 × 10 3  kg of 305-day milk production), DMP3 (dams with ≥12.00 × 10 3  kg and <14.00 × 10 3  kg of 305-day milk production), DMP4 (dams with ≥14.00 × 10 3  kg and <16.00 × 10 3  kg of 305-day milk production) and DMP5 (dams with ≥16.00 × 10 3  kg of 305-day milk production). In study I, data of birth weight, milk yield and reproductive variables of 14,536 offspring born to lactating dams and corresponding data of DMP were retrieved. In study II, blood samples (n = 339) were collected from offspring in various categories of DMP for measurement of serum AMH. Offspring were heavier at birth in DMP4 and DMP5 categories than DMP1 and DMP2 categories (P < 0.05). Milk yield of offspring increased as DMP elevated (P < 0.05); however, offspring in DMP1 and DMP2 categories produced higher milk as compared with their dams during primiparity (P < 0.05) whereas offspring in DMP3, DMP4 and DMP5 categories produced less milk as compared with their dams during primiparity (P < 0.05). Milk fat to protein ratio during the first month of lactation was greater in DMP4 and DMP5 categories than DMP1 category (P < 0.05). Offspring of DMP4 and DMP5 categories were inseminated and conceived at younger ages than offspring of DMP1 category during nulliparity (P < 0.05). Calving to conception interval was longer in DMP5 than DMP1 category in primiparous offspring (P < 0.05), but concentration of AMH did not differ among various categories of DMP (P > 0.05). In conclusion, dams with greater level of milk production produced heavier offspring with higher milk yield but worse transgenerational improvement in milk production and diminished reproductive performance, which were seemingly under higher pressure of negative energy balance during the first month of lactation., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Summary: We report the emergence of an endogenous circadian clock that regulates organogenesis in mouse fetal kidney. We detect circadian rhythms both in vivo with transcriptional profiling and ex vivo by bioluminescence. High-resolution structural analysis of embryonic explants reveals that global or local clock disruption results in defects that resemble human congenital abnormalities of the kidney. The onset of fetal rhythms strongly correlates with the timing of a distinct transition in branching and growth rates during a gestational window of high fetal growth demands. Defects in clock mutants typically have been attributed to accelerated aging; however, our study establishes a role for the fetal circadian clock as a developmental timer that regulates the pathways that control organogenesis, branching rate, and nephron number and thus plays a fundamental role in kidney development.

Feeding dried distillers grains with solubles (DDGS), a feed high in fat and protein, to lactating beef cows can alter milk production and composition, resulting in improved pre-weaning growth of progeny. This alteration in milk profile may consequently alter the growth and carcass composition of the offspring after weaning. Therefore, Angus×Simmental steers (n=48) whose dams were fed one of two diets supplemented with either DDGS or soybean meal (CON) from calving to mid-lactation were placed in a feedlot to determine the effects of maternal nutrition during lactation on progeny development and carcass composition. Cow–calf pairs were allotted to two treatments at birth based on cow and calf BW, breed and age. Maternal diets were isocaloric (3.97 MJ/kg NEg) and consisted of rye hay supplemented with DDGS at 1% of BW (19.4% CP; 8.76% fat) or rye hay and corn silage supplemented with CON (11.7% CP; 2.06% fat). After conclusion of the treatments at 129 days postpartum, cow–calf pairs were comingled and managed as one group until weaning at 219 days postpartum. Steers were then transitioned to a common diet composed of 60% DDGS, 34% corn silage and 6% vitamin/mineral supplement and were placed indoors in individual pens with slatted floors. An intravenous glucose tolerance test (IVGTT) was performed 134 days after feedlot entry on 16 steers (CON, n=7; DDGS, n=9) to determine the effect of maternal diet on glucose and insulin sensitivity. Steers were slaughtered at a target BW of 645 kg. Categorical and continuous data were analyzed using the GLIMMIX and MIXED procedures of SAS, respectively. Steers from DDGS dams tended to be heavier on day 85 of feedlot finishing (P=0.09) compared with steers from CON dams. However, there were no differences in final weight, average daily gain, dry matter intake or efficiency (gain:feed, P⩾0.18). Maternal treatments did not affect progeny days on feed (P=0.15), despite a mean difference of 9 days in favor of DDGS. Glucose and insulin concentrations and area under the curve of progeny as measured by IVGTT were not affected by maternal diet (P⩾0.16). Maternal DDGS supplementation decreased marbling score (P=0.04), but did not influence carcass grading percentage or any other carcass characteristic (P⩾0.17).

Although the negative effect of maternal exposure to heat stress on production and reproduction of offspring has been reported, there are some discrepancies among various studies about which gestational stage is more critical in this regard. Therefore, the present research was conducted to identify during which stage(s) of pregnancy maternal exposure to heat stress would lead to more dramatic decrease in productive and reproductive performance of offspring. To this end, offspring were classified based on the gestational stage they were in utero exposed to heat stress into four categories, including heat stress exposure (HSE) during only the first trimester of gestation (HSE1), HSE during the first and second trimester of gestation (HSE2), HSE during the second and third trimester of gestation (HSE3) and HSE during only the third trimester of gestation (HSE4). In study I, data of birth weight, milk yield and reproductive variables of 11,788 offspring and data of the month they were conceived were retrieved. In study II, blood samples (n = 521) were collected from offspring in various categories of HSE for measurement of serum AMH. Offspring in HSE1 and HSE2 categories were heavier than offspring in HSE3 and HSE4 categories (P < 0.0001). Offspring in HSE1 and HSE3 categories had the lowest and highest milk production, respectively (P < 0.05). First service conception rate was the greatest and worst in HSE1 and HSE4 categories, respectively (P < 0.05). Service per conception and calving to conception interval were greater in HSE2 than HSE4 category (P < 0.05). Concentration of AMH was lower in HSE1 than HSE4 category (P < 0.05). In conclusion, the present study indicated that the early stage of gestation could be a more critical period for the negative impact of in utero heat stress on developmental programming of milk production and ovarian reserves. Yet an evident temporal pattern for the adverse effect of maternal heat stress on developmental programming of reproductive performance in offspring was not found., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Multiparous Angus×Simmental cows (n=54, 5.22±2.51 years) with male progeny were fed one of two diets supplemented with either dried distillers grains with solubles (DDGS) or soybean meal (CON), from calving until day 129 postpartum (PP) to determine effects of excess protein and fat on cow performance, milk composition and calf growth. Diets were formulated to be isocaloric and consisted of rye hay and DDGS (19.4% CP; 8.76% fat), or corn silage, rye hay and soybean meal (11.7% CP; 2.06% fat). Cow–calf pairs were allotted by cow and calf age, BW and breed. Cow BW and body condition score (BCS; P⩾0.13) were similar throughout the experiment. A weigh-suckle-weigh was performed on day 64 and day 110±10 PP to determine milk production. Milk was collected on day 68 and day 116±10 PP for analysis of milk components. Milk production was unaffected (P⩾0.75) by dietary treatments. Milk urea nitrogen was increased at both time points in DDGS compared with CON cows (P

Multiparous dams have been reported to produce offspring with greater fertility and higher AMH concentration, as a marker of ovarian reserves, as compared with nulliparous and primiparous dams. Yet it has remained to be addressed whether this phenomenon can still be true for old multiparous cows which might experience some geriatric changes in their reproductive system. Therefore, the present study was conducted to evaluate the productive and reproductive performance of offspring with different maternal parity. To this end, offspring were classified based on their maternal parities into four categories, including offspring of nulliparous (no previous parity), primiparous (one previous parity), young multiparous (two to six previous parities) and old multiparous (seven or more previous parities) dams. In study I, data of birth weight, milk yield and reproductive variables of 11,788 offspring and data of their maternal parity were retrieved. In study II, blood samples (n = 521) were collected from offspring with various maternal parity for measurement of serum AMH. Birth weight was the lowest in the offspring of nulliparous dams (P < 0.0001) and it was lower in offspring of primiparous and old multiparous dams than offspring of young multiparous dams (P < 0.05). Milk production was the lowest in offspring of old multiparous dams (P < 0.01), and it was lower in offspring of young multiparous dams than offspring of nulliparous and primiparous dams (P < 0.0001). Offspring of old multiparous dams had greater first service conception rate, less services per conception and shorter calving to conception interval than offspring of nulliparous, primiparous and young multiparous dams (P < 0.05). Furthermore, AMH concentration was higher in offspring of old multiparous dams than offspring of nulliparous and primiparous dams (P < 0.05). In conclusion, the present study revealed greater milk production in offspring resulting from dams with lower parity, probably due to the genetic selection for improvement of milk production in dairy cows which imparts the younger generations greater genetic merits for milk production. Reproductive performance, however, was greater in offspring born to dams with higher parity, particularly those born to old multiparous dams, and this phenomenon might be related to their lower milk production and higher AMH concentration., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In ovo corticosterone (CORT) exposure reportedly reduces growth and alters body composition traits in meat-type chickens. However, the mechanisms governing alterations in growth and body composition remain unclear but could involve myogenic stem cell commitment, and/or the presence of yolk steroid hormones. This study investigated whether in ovo CORT exposure influenced yolk steroid hormone content, as well as embryonic myogenic development in meat-type chickens. Fertile eggs were randomly divided at embryonic day (ED) 11 and administered either a control (CON; 100 µL of 10 mM PBS) or CORT solution (100 µL of 10 mM PBS containing 1 µg CORT) into the chorioallantoic membrane. Yolk samples were collected at ED 0 and ED 5. At ED 15 and hatch, embryos were humanely killed, and yolk and breast muscle (BM) samples were collected. The relative abundance of 15 steroid hormones, along with total lipid content was measured in yolk samples collected at ED 0, ED 5, ED 15, and ED 21. Muscle fiber number, cross-sectional area, and fascicle area occupied by muscle fibers were measured in BM samples collected at hatch. Relative expression of MyoD, MyoG, Pax7, PPARγ, and CEBP/β, and the sex steroid receptors were measured in BM samples collected at hatch. The administration of CORT had a limited effect on yolk steroid hormones. In ovo CORT significantly reduced fascicle area occupied by muscle fibers and CEBP/β expression was increased in CORT exposed birds at hatch. In addition, the quantity of yolk lipid was significantly reduced in CORT-treated birds. In conclusion, in ovo exposure to CORT does not appear to influence early muscle development through yolk steroid hormones in embryonic meat-type chickens however, the results provide a comprehensive analysis of the composition of yolk steroid hormones in ovo at different developmental time points. The findings may suggest increased mesenchymal stem cell commitment to the adipogenic lineage during differentiation and requires further investigation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Extremely premature infants are often exposed to supra-physiologic concentrations of oxygen, and frequently have hypoxemic episodes. These preterm infants are at high risk (~40%) for neurodevelopmental impairment (NDI) even in the absence of obvious intracranial pathology such as intraventricular hemorrhage or periventricular leukomalacia. The etiology for NDI has not been determined, and there are no animal models to simulate neurodevelopmental outcomes of prematurity. Our objectives were to develop and characterize a mouse model to determine long-term effects of chronic hypoxia or hyperoxia exposure on neurodevelopment. Newborn C57BL/6 mice were exposed to hypoxia (12% O2) or hyperoxia (85% O2) from postnatal days 1 to 14 and then returned to air. At 12–14 weeks of age, neurobehavioral assessment (Water Maze test, Novel Object Recognition test, Open Field test, Elevated Plus Maze, and Rotarod test) was performed, followed by MRI and brain histology. Neurobehavioral testing revealed that hyperoxia-exposed mice did poorly on the water maze and novel object recognition tests compared to air-exposed mice. MRI demonstrated smaller hippocampi in hyperoxia- and hypoxia-exposed mice with a greater reduction in hyperoxia-exposed mice, including a smaller cerebellum in hyperoxia-exposed mice. Brain histology showed reduced CA1 and CA3 and increased dentate gyral width in hippocampus. In conclusion, neonatal hyperoxia in mice leads to abnormal neurobehavior, primarily deficits in spatial and recognition memory, associated with smaller hippocampal sizes, similar to findings in ex-preterm infants. This animal model may be useful to determine mechanisms underlying developmental programming of NDI in preterm infants, and for evaluation of therapeutic strategies.

Women who were themselves small-for-gestational age (SGA) are at a greater risk of adulthood diseases such as non-insulin-dependent diabetes mellitus (NIDDM), and twice at risk of having an SGA baby themselves. The aim of this study was to examine the intergenerational pig. Low (L) and normal (N) birth weight female piglets were followed throughout their first pregnancy (generation 1 (G1)). After they had given birth, the growth and development of the lightest (l) and heaviest (n) female piglet from each litter were monitored until approximately 5 months of age (generation 2 (G2)). A glucose tolerance test (GTT) was conducted on G1 pig at ∼6 months of age and again during late pregnancy; a GTT was also conducted on G2 pigs at ∼4 months of age. G1 L offspring exhibited impaired glucose metabolism in later life compared to their G1 N sibling but in the next generation a similar scenario was only observed between l and n offspring born to G1 L mothers. Despite G1 L mothers showing greater glucose intolerance in late pregnancy and a decreased litter size, average piglet birth weight was reduced and there was also a large variation in litter weight; this suggests that they were, to some extent, prioritising their nutrient intake towards themselves rather than promoting their reproductive performance. There were numerous relationships between body shape at birth and glucose curve characteristics in later life, which can, to some extent, be used to predict neonatal outcome. In conclusion, intergenerational effects are partly seen in the pig. It is likely that some of the intergenerational influences may be masked due to the pig being a litter-bearing species.

Increasing rates of obesity and heart disease are compromising quality of life for a growing number of people. There is much research linking adult disease with the growth and development both in utero and during the first year of life. The pig is an ideal model for studying the origins of developmental programming. The objective of this paper was to construct percentile growth curves for the pig for use in biomedical studies. The body weight (BW) of pigs was recorded from birth to 150 days of age and their crown-to-rump length was measured over the neonatal period to enable the ponderal index (PI; kg/m3) to be calculated. Data were normalised and percentile curves were constructed using Cole’s lambda-mu-sigma (LMS) method for BW and PI. The construction of these percentile charts for use in biomedical research will allow a more detailed and precise tracking of growth and development of individual pigs under experimental conditions.

Although the effect of mastitis on reproduction and production of lactating dairy cows has been vastly studied, little information is available about the association of maternal udder health status with offspring reproduction and production. Therefore, the present research was conducted to study the association between maternal average monthly somatic cell count (SCC) with reproduction, anti-Müllerian hormone (AMH) concentration, udder health status and milk production in the offspring. Based on maternal average monthly SCC (MSCC), offspring were classified into five categories including MSCC1 (SCC <200,000; n = 3005), MSCC2 (200,000 ≤ SCC <400,000; n = 252), MSCC3 (400,000 ≤ SCC <600,000; n = 103), MSCC4 (600,000 ≤ SCC <800,000; n = 40) and MSCC5 (SCC ≥800,000; n = 61). Data associated with reproduction, production and udder health status of offspring were retrieved from the herd database. In addition, blood samples were collected from a subset of offspring (n = 136) for measurement of serum AMH, as a reliable marker of ovarian reserves. Offspring in MSCC5 category had more services per conception and longer calving to conception interval than offspring in MSCC1 and MSCC2 categories (P < 0.05). The average number of SCC and risk of clinical mastitis in the offspring were not associated with MSCC (P > 0.05). But offspring in MSCC5 category produced less milk, fat and protein than offspring in MSCC1 category (P < 0.05). In addition, AMH concentration was lower in MSCC5 than MSCC1 category (P < 0.05). In conclusion, the present study showed that elevated maternal average monthly SCC could culminate in birth of offspring with inferior reproductive performance, smaller size of ovarian reserves and lower level of milk production during the first lactation period., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Recent evidence in humans and animals indicates an association between maternal obesity and offspring behavioral outcomes. In humans, increased maternal body mass index has been linked to an increased risk of children receiving a diagnosis of early-emerging neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and/or Autism Spectrum Disorder (ASD). However, a limited number of preclinical studies have examined associations between maternal Western-Style Diet (mWSD) exposure and offspring social behavior. To our knowledge, this is the first study to investigate relationships between mWSD exposure and social behavior in non-human primates. Since aberrant social behavior is a diagnostic criterion for several neurodevelopmental disorders, the current study focuses on examining the influence of maternal nutrition and metabolic state on offspring social behavior in Japanese macaques (Macaca fuscata). We found that mWSD offspring initiated less affiliative social behaviors as well as proximity to a peer. Using path analysis, we found that the association between mWSD consumption and reduced offspring social engagement was statistically mediated by increased maternal interleukin (IL)-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin in the third trimester. Together, these results suggest that NHP offspring exposed to mWSD exhibit behavioral phenotypes similar to what is described in some early-emerging neurodevelopmental disorders. These results provide evidence that mWSD exposure during gestation may be linked to increased risk of neurodevelopmental disorders and provides targets for prevention and intervention efforts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This review summarizes the latest findings, from animal models and clinical studies, regarding the cardiovascular and metabolic consequences in adult life of zinc deficiency (ZD) during prenatal and early postnatal life. The effect of zinc supplementation (ZS) and new insights about sex differences in the phenotype and severity of cardiovascular and metabolic alterations are also discussed. Zinc has antioxidant, anti-inflammatory, and antiapoptotic properties and regulates the activity of enzymes involved in regulation of the metabolic, cardiovascular, and renal systems. Maternal ZD is associated with intrauterine growth restriction and low birth weight (LBW). Breast-fed preterm infants are at risk of ZD due to lower zinc uptake during fetal life and reduced gut absorption capacity. ZS is most likely to increase growth in preterm infants and survival in LBW infants in countries where ZD is prevalent. Studies performed in rats revealed that moderate ZD during prenatal and/or early postnatal growth is a risk factor for the development of hypertension, cardiovascular and renal alterations, obesity, and diabetes in adult life. An adequate zinc diet during postweaning life does not always prevent the cardiovascular and metabolic alterations induced by zinc restriction during fetal and lactation periods. Male rats are more susceptible to this injury than females, and some of the mechanisms involved include: 1) alterations in organogenesis, 2) activation of oxidative, apoptotic, and inflammatory processes, 3) dysfunction of nitric oxide and renin-angiotensin-aldosterone systems, 4) changes in glucose and lipid metabolism, and 5) adipose tissue dysfunction. Safeguarding body zinc requirements during pregnancy, lactation, and growth periods could become a new target in the prevention and treatment of cardiovascular and metabolic disorders. Further research is needed to elucidate the efficacy of ZS during early stages of growth to prevent the development of these diseases later in life., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The concept of developmental programming suggests that maternal excessive energy intake during intrauterine development could permanently affect the offspring's performance. Spirulina might alleviate adverse programming effects, but currently has only been shown to affect productivity and product quality of livestock when fed directly. Therefore, we investigated effects of supplementing 20 g spirulina/day to 20 gestating and lactating sows fed either a commercial or a high energy diet (HED), on performance and meat quality of their piglets fattened for 4 months. Control and HED offspring did not differ in growth and slaughter performance. Maternal spirulina supplementation impaired growth performance in male but not in female offspring. Physicochemical meat quality was not affected by any treatment. Maternal spirulina intake tended to improve the polyunsaturated fatty acids (FA)/saturated FA ratio without affecting n-6/n-3 FA ratio in offspring meat. The present findings indicate a sex-specific programming effect for offspring growth in response to maternal spirulina but not high energy intake in pigs., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The persistent endocrinological effects of perinatal stress due to gestational immaturity in horses are unknown, although effects have been reported in other livestock species. This pilot study tested the hypothesis that persistent adrenocortical dysregulation is present in horses that were gestationally immature at birth by assessing the salivary cortisol response to exogenous ACTH. Case horses (n = 10) were recruited with histories of gestation length < 315 d or dysmaturity observable through neonatal signs. Positive controls (n = 7) and negative controls (n = 5) were recruited where possible from related horses at the same locations. Cases and positive controls received an intramuscular, low-dose (0.1 ug/kg) of synthetic ACTH (Tetracosactrin 250 mg/mL, Synacthen); negative controls received no ACTH. Saliva samples were collected from all horses at baseline T = 0 and at 30 min intervals post injection from T = 30 to T = 150. These were assayed for salivary cortisol concentration (SCC) using a commercially available ELISA kit (Salimetrics). All baseline values (T = 0) were within normal published ranges. Peak and AUC values (corrected for baseline) for case horses were significantly different (ANOVA P < .001) to positive controls, with either higher (H-cases) or lower (L-cases) SCC values, outside the 95% Confidence Interval of the reference population. There was no significant effect of breed, age, sex, test month, or location on results. The results suggest that gestational immaturity may lead to subclinical adrenocortical dysregulation, with affected horses presenting an elevated or blunted response to a low-dose ACTH stimulation, despite normal basal levels., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Stress in pregnancy is associated with adverse outcomes in offspring, and developmental programming is a potential mechanism. We have previously shown that depression in pregnancy is a valid and clearly defined stress paradigm, and both maternal antenatal and offspring stress-related biology is affected. This study aims to clarify whether maternal biology in pregnancy and offspring outcomes can also be influenced by a history of a prior depression, in the absence of depression in pregnancy. Our primary hypothesis is that, similarly to women with depression in pregnancy, women with a history of depression but who are not depressed in pregnancy will have increased cortisol secretion and markers of immune system function, and that their offspring will have poorer neuro-developmental competencies and increased cortisol stress response., Methods: A prospective longitudinal design was used in 59 healthy controls and 25 women with a past history of depression who were not depressed in pregnancy, named as 'history-only', and their offspring. Maternal antenatal stress-related biology (cortisol and markers of immune system function) and offspring outcomes (gestational age at birth, neonatal neurobehaviour (Neonatal Behavioural Assessment Scale, NBAS), cortisol stress response and basal cortisol at 2 and 12 months) and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development (BSID)) were measured., Results: Compared with healthy pregnant women, those with a history of depression who remain free of depression in pregnancy exhibit increased markers of immune system function in pregnancy: IL-8 (d = 0.63, p = 0.030), VEGF (d = 0.40, p = 0.008) and MCP-1 (d = 0.61, p = 0.002) and have neonates with lower neurobehavioural scores in most areas, reaching statistical significance in thesocial-interactive (d = 1.26, p = 0.015) cluster. However, there were no differences in maternal or offspring HPA axis function or in infant development at 12 months., Conclusion: Our study indicates that pregnant women with a history of depression have increased markers of immune system function, and their offspring show behavioural alterations that may be the effects of in utero programming, epigenetic factors or genetic predisposition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Despite the indispensable role of the placenta in the successful course of pregnancy, regulation of its dynamic transcriptome is still underexplored. The purpose of this literature review was to give an overview and draw attention to the contribution of genetic variation in shaping the human placental gene expression. Studies of placental transcriptome shaped by chromosomal variants are limited and may be confounded by cellular mosaicism and somatic genomic rearrangements. Even in relatively simple cases, such as aneuploidies, the placental transcriptome appears to differ from the assumed systematically increased transcript levels of the involved chromosomes. Single nucleotide variants modulating placental gene expression referred to as expression quantitative trait loci (eQTLs) have been analyzed only in ten candidate gene and three genome-wide association studies (GWAS). The latter identified 417 confident placental eGenes, supported by at least two independent studies. Functional profiling of eGenes highlighted biological pathways important in pregnancy, such as immune response or transmembrane transport activity. A fraction of placental eQTLs (1-3%) co-localize with GWAS loci for adult disorders (metabolic, immunological, neurological), suggesting a co-contributory role of the placenta in the developmental programming of health. Some placental eQTLs have been identified as risk factors for adverse pregnancy outcomes, such as rs4769613 (C > T), located near the FLT1 gene and confidently associated with preeclampsia. More studies are needed to map genetic variants shaping gene expression in different placental cell types across three trimesters in normal and complicated gestations and to clarify to what extent these heritable factors contribute to maternal and offspring disease risks., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Our objectives were to determine the effects of dam body condition score (BCS), age of dam, and calf sex on placental size and the relationships between dam body weight (BW) and calf size with placental size. Expelled placentas and calf size at birth were collected from crossbred beef heifers and cows during four experiments (n = 22 to 39/experiment). Placentas deemed complete by visual inspection were dissected; dry weights were determined for cotyledonary and intercotyledonary tissues. Mixed linear models were used to individually determine main effects of peripartum BCS category [Thin (<5), Moderate (=5), or Fleshy (≥6)], age of dam category [Primiparous (2 yr), Young (3-4 yr), or Mature (≥5 yr)], and calf sex on placental measures. Correlations were determined for placental characteristics with prepartum dam BW, gestation length, and calf size. Thin BCS dams had lower (P ≤ 0.05) cotyledonary, total placental, and average cotyledon weights and greater placental efficiency (calf birth BW/placental weight) than moderate and fleshy dams. Intercotyledonary weight was lower (P < 0.01) in thin BCS dams compared with fleshy dams. Thin and moderate BCS dams had smaller (P ≤ 0.04) calf birth BW than fleshy dams. Primiparous dams had lower (P ≤ 0.05) total placental and average cotyledon weights than young and mature dams, yet calf birth BW was unaffected (P = 0.17). Male calves were heavier (P = 0.01) than females, yet there were no differences (P ≥ 0.59) in placental weights. Calf birth BW and heart girth had moderate positive correlations (P < 0.01) and shoulder to rump length and abdominal girth had weak positive correlations (P < 0.01) with all placental weights. Dam prepartum BW and calf flank girth had moderate positive correlations (P < 0.01) with total placental weights and weak positive correlations (P < 0.01) with cotyledonary and average cotyledon weights. Intercotyledonary weight had moderate positive correlations (P < 0.01) with gestation length and calf flank girth and a weak positive correlation (P < 0.01) with dam prepartum BW. Gestation length had a weak positive correlation (P = 0.02) with total placental weight. Number of cotyledons was not correlated (P ≥ 0.28) with any dam or offspring characteristics. In conclusion, these data suggest that both maternal age and BCS affected placental size. Calf size at birth and placental weight were positively correlated, but it is still unknown which controls and signals for the growth of the other., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Skeletal muscle plays an integral role in the ability of a horse to perform at high levels. Shifts in skeletal muscle development in response to maternal plane of nutrition may have substantial and lasting impacts on athletic performance and whole-body metabolism. Therefore, sixteen Quarter Horse mares were used in a completely randomized design and maintained at a body condition score (BCS) 6 until start of third trimester. On d 235 of gestation, mares were randomly assigned to receive one of two dietary treatments with a diet formulated to meet requirements during late gestation (CON; n = 8), and an overfed diet (HIGH; n = 8) where mares received an additional 40% above CON. Five h after parturition, foals were euthanized, and gluteus medius, triceps brachii, and semitendinosus were harvested for analyses. Gene expression was determined by qPCR and western immunoblotting was used to quantify total and phosphorylated forms of proteins involved in skeletal muscle metabolism with tubulin as the loading control. All data were analyzed using PROC MIXED of SAS. Foals from HIGH mares exhibited larger skeletal muscle fibers by area (P <0.05), and a shift in muscle fiber development towards type I slow twitch muscle fibers (P <0.05). Relative expression of glucose transporter 4 (GLUT4) was lower in HIGH foals compared to CON in gluteus medius (P = 0.05). Insulin receptor isoform B (INSR-B) and insulin-like growth factor 1 receptor (IGF1R) were greater in triceps brachii of HIGH foals compared to CON (P ≤ 0.03). Insulin receptor isoform A (INSR-A), however, tended to be lower in triceps brachii of HIGH compared to CON (P = 0.10). Ratios of phosphorylated to total extracellular signal-regulated protein kinase 1/2 (ERK1/2) and c-June N-terminal kinase (JNK) were higher in HIGH foals compared to CON (P ≤0.04) in gluteus medius. There were no differences observed for phosphorylated to total protein ratios in semitendinosus and triceps brachii muscles; however, total ERK1/2 tended to be elevated (P <0.10) in semitendinosus from CON foals compared to HIGH. There was no difference in phosphorylated or total protein kinase B (AKT) (P >0.14). These data indicate hypertrophy of skeletal muscle fibers and a shift towards type I slow twitch fibers in HIGH foals. Furthermore, this study identifies muscle specific changes in gene expression and downstream insulin receptor signaling, which may contribute to future metabolic abnormalities in response to maternal overnutrition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Male infertility and reproductive dysfunctions have become major global health problems. Although several causative factors have been attributed to this challenge, of importance are alterations in maternal-foetal environment, diet-induced transcriptional changes and dysregulation in chemical signaling via hypothalamic-gonadal axis., Aim: The present study investigated the impact of maternal high-fat diet (HFD) consumption and the putative role of Quercetin-3-O-rutinoside on reproductive functions of male offspring rats at critical developmental stages with a quest to unravel the underpinned molecular changes., Materials and Methods: Fifty-six pregnant rats (previously fed normal diet ND) or 45% HFD) were maintained on supplemented chow (150 mg/kg QR) - ND/QR, HFD/QR throughout gestation. Subsequently, dams (n = 7) and offspring (n = 6) were sacrificed at post-natal day (PND) 21, 28 and 35, respectively, and the blood, placenta, hypothalamus (HT), and testicular samples were processed for molecular analysis of Gonadotropin-releasing hormone (GnRH), Luteinizing hormone (LH), testosterone, chemerin, chemokine-like receptor 1 (CMKLR1), tumour necrosis factor α (TNF-α), interleukin 1β (IL-1β) and nuclear factor kappa B (NF-κB)., Key Findings: We observed a significant decrease in GnRH level in the HFD group at PND21 and PND28 in male offspring and treatment with QR significantly reduced GnRH. There was a significant reduction in LH levels in the HFD group at PND 21 in the male offspring accompanied by a significant decrease in testosterone level at PND 28 and PND35 which appears to be age dependent. In the HT, Chemerin and CMKLR1 was significantly upregulated in the HFD group at PND 21 and PND 35 respectively while CMKLR1 was significantly downregulated in the HFD group of the placenta and testis at PND 21. TNF-α, IL-1β and NF-κB were also expressed in the placenta, HT and testis at PND 21., Significance: Male fertility is affected by maternal HFD consumption while chemerin, CMKLR1 and TNF-α, may play a significant role in male steroidogenesis. Treatment with QR had little or no ameliorative effect on HFD induced alterations in male reproductive functions., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The birth rates among women of advanced maternal age (AMA) have risen over the last two decades; yet, pregnancies with AMA are considered high-risk and are associated with a significant increase in pregnancy complications. Although the mechanisms leading to pregnancy complications in women with AMA are not fully understood, it has been well established in the literature that offspring exposed to unfavorable environmental conditions in utero, such as gestational diabetes, preeclampsia, and/or intrauterine growth restriction during the early stages of development are subject to long-term health consequences. Additionally, angiogenic growth mediators, which drive vascular development of the placenta, are imbalanced in pregnancies with AMA. These same imbalances also occur in pregnancies complicated by preeclampsia, gestational diabetes, and obesity. This review discusses the impact of AMA on pregnancy and offspring health, and the potential mechanistic role of placental angiogenic growth mediators in the development of pregnancy complications at AMA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The development of personality pathology is an interactive process between biologically based susceptibilities, interpersonal patterns, and contextual factors across the lifespan. In this paper, we argue that these interactions begin before birth. We describe the perinatal period (i.e. pregnancy and up to one year postpartum) as a sensitive developmental window during which regulatory and stress response systems that confer risk for personality pathology begin forming. In addition, we present converging evidence for significant associations between perinatal factors and later life personality disorders. Finally, we present this perinatal perspective through the lens of dynamical systems theory and emphasize the promise of this framework for guiding future personality disorder research, prevention, and intervention., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Paternal low-protein diet can alter sperm methylation status, fetal growth and program offspring ill-health, however its impact on the placenta remains poorly defined. Here we examine the influence paternal low-protein diet has on fetal and placental development and the additional impact of supplementary methyl-donors on fetoplacental physiology., Methods: Male C57BL/6J mice were fed a control normal protein diet (NPD; 18% protein), a low-protein diet (LPD; 9% protein) or LPD with methyl-donor supplementation (MD-LPD; choline chloride, betaine, methionine, folic acid, vitamin B12) for a minimum of 8 weeks. Males were mated with 8-11 week old female C57BL/6J mice and fetal and placental tissue collected on embryonic day 17.5., Results: Paternal LPD was associated with increased fetal weights compared to NPD and MD-LPD with 22% fetuses being above the 90th centile for fetal weight. However, LPD and MD-LPD placental weights were reduced when compared to NPD. Placentas from LPD fathers demonstrated a reduced junctional zone area and reduced free-fatty acid content. MD-LPD placentas did not mirror these finding, demonstrating an increased chorion area, a reduction in junctional-specific glycogen staining and reduced placental Dnmt3bexpression, none of which were apparent in either NPD or LPD placentas., Discussion: A sub-optimal paternal diet can influence fetal growth and placental development, and dietary methyl-donor supplementation alters placental morphology and gene expression differentially to that observed with LPD alone. Understanding how paternal diet and micro-nutrient supplementation influence placental development is crucial for determining connections between paternal well-being and future offspring health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The objective of this experiment was to evaluate the effects of nutrient restriction and melatonin supplementation during mid-to-late gestation on maternal and fetal small intestinal carbohydrase activities in sheep. Ewes were randomly assigned to one of 4 dietary treatments arranged in a 2 × 2 factorial design. Ewes were fed to provide 100% (adequate; ADQ) or 60% (restricted; RES) of nutrient recommendations, and diets were supplemented with either no melatonin (control; CON) or 5 mg melatonin/d (melatonin; MEL). This resulted in 4 treatment groups: CON-ADQ (n = 7), CON-RES (n = 8), MEL-ADQ (n = 8), MEL-RES (n = 8). Treatments began on day 50 of gestation, and ewes were euthanized on day 130 for tissue collection. The maternal and fetal small intestine were collected and assayed for small intestinal carbohydrase activities. Data were analyzed using the GLM procedure of SAS with fetal sex, melatonin, nutrition, and the melatonin by nutrition interaction included in the model statement. There were no melatonin by nutrition interactions for maternal or fetal small intestinal protein concentration or carbohydrase activities (P ≥ 0.11). Dietary melatonin supplementation decreased (P = 0.03) maternal small intestinal protein concentration by 22.7% and increased (P = 0.03) maternal small intestinal glucoamylase, isomaltase, and maltase activity per gram protein by 45.5%, 41.3%, and 40.6%, respectively. Nutrient restriction from mid-to-late gestation did not influence (P ≥ 0.46) maternal small intestinal protein concentration, or maltase, isomaltase, and lactase activity. Maternal glucoamylase activity per gram intestine increased (P = 0.05) with nutrient restriction by 49.1%. Melatonin supplementation and maternal nutrient restriction did not influence (P ≥ 0.15) fetal small intestinal protein concentration, or glucoamylase, isomaltase, and lactase activity. Maternal nutrient restriction from mid-to-late gestation decreased (P = 0.05) fetal maltase activity per gram intestine by 20.5% but did not influence fetal maltase activity per gram protein. These data indicate that some maternal and fetal carbohydrases are influenced by nutrient restriction and melatonin supplementation in sheep. More information is needed to understand how nutritional and hormonal factors regulate digestive enzyme activity in ruminants to design improved maternal nutrition programs to optimize fetal growth and development while maintaining maternal productivity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

To determine the influence of maternal nutrient restriction and rumen-protected arginine supplementation on post-ruminal digestive enzyme activity in lambs, 31 multiparous, Rambouillet ewes were allocated to one of three dietary treatments at 54 d of gestation. Dietary treatments were 100% of nutrient requirements (control, CON; n = 11), 60% of control (restricted, RES; n = 10), or RES plus 180 mg rumen-protected arginine•kg BW -1 •d -1 (RES-ARG; n = 10). Immediately after parturition, lambs were removed from dams and reared independently. Milk-replacer and alfalfa hay + creep feed were offered for ad libitum intake. At day 54 of age, lambs were slaughtered and the pancreas and small intestine were collected. Pancreatic (α-amylase and trypsin) and jejunal (maltase, glucoamylase, sucrase, isomaltase, and lactase) digestive enzyme activities were assayed. Data were analyzed using the GLM procedure of SAS for effects of treatment. Contrast statements were used to determine differences between means for effects of restriction (CON vs. RES and RES-ARG) and rumen-protected arginine supplementation (RES vs. RES-ARG). There was no influence ( P ≥ 0.15) of maternal nutrient restriction or rumen-protected arginine supplementation on pancreatic or jejunal protein concentrations. No treatment effects were observed ( P ≥ 0.12) for enzymes involved in starch digestion including pancreatic α-amylase and jejunal maltase, glucoamylase, and isomaltase. Sucrase activity was undetected in the jejunum of lambs across all treatments. Maternal nutrient restriction tended to increase ( P = 0.08) pancreatic trypsin activity per gram protein in lambs. Lactase activity per gram protein in the jejunum of lambs tended to decrease ( P = 0.09) with maternal nutrient restriction. Rumen-protected arginine supplementation to gestating ewes did not influence ( P ≥ 0.19) digestive enzyme activities of lamb offspring. These data suggest that maternal nutrient restriction and rumen-protected arginine supplementation have minimal effects on digestive enzyme activity in offspring.

Maternal obesity during pregnancy is associated with a greater risk for obesity and neurodevelopmental deficits in offspring. This developmental programming of disease is proposed to involve neuroendocrine, inflammatory, and epigenetic factors during gestation that disrupt normal fetal brain development. The hormones leptin and insulin are each intrinsically linked to metabolism, inflammation, and neurodevelopment, which led us to hypothesise that maternal obesity may disrupt leptin or insulin receptor signalling in the developing brain of offspring. Using a C57BL/6 mouse model of high fat diet-induced maternal obesity (mHFD), we performed qPCR to examine leptin receptor (Lepr) and insulin receptor (Insr) gene expression in gestational day (GD) 17.5 fetal brain. We found a significant effect of maternal diet and offspring sex on Lepr regulation in the developing hippocampus, with increased Lepr expression in female mHFD offspring (p < 0.05) compared to controls. Maternal diet did not alter hippocampal Insr in the fetal brain, or Lepr or Insr in prefrontal cortex, amygdala, or hypothalamus of female or male offspring. Chromatin immunoprecipitation revealed decreased binding of histones possessing the repressive histone mark H3K9me3 at the Lepr promoter (p < 0.05) in hippocampus of female mHFD offspring compared to controls, but not in males. Sex-specific deregulation of Lepr could be reproduced in vitro by exposing female hippocampal neurons to the obesity related proinflammatory cytokine IL-6, but not IL-17a or IFNG. Our findings indicate that the obesity-related proinflammatory cytokine IL-6 during pregnancy leads to sexually dimorphic changes in the modifications of histones binding at the Lepr gene promoter, and concomitant changes to Lepr transcription in the developing hippocampus. This suggests that exposure of the fetus to metabolic inflammatory molecules can impact epigenetic regulation of gene expression in the developing hippocampus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)