The effect of smoking and nicotine exposure during pregnancy on fetal nephrogenesis is a growing area of research. The objective of this systematic review is to summarise the current evidence in this research field. Our literature search identified a total of 415 articles from PubMed, Embase, Scopus, and Cochrane. After electronic sorting and manual screening, 18 eligible articles were found, 6 being human studies and 12 being animal studies. Articles that did not study nicotine or smoking, did not focus on fetal kidney development, or did not include nicotine or smoking exposure during pregnancy were excluded from the systematic review. The main outcomes of the studies were kidney weight, volume and size, kidney histopathology and morphology, and kidney function. Evidence from human studies identified a reduction in fetal kidney size, volume, and weight in offspring exposed to smoking during pregnancy; and the greatest impact was seen in offspring exposed to >5–10 cigarettes per day. Animal studies investigated kidney histopathology and highlighted kidney injury and microscopic changes in response to nicotine exposure during pregnancy. Further research is required to determine the impact on kidney function. Recreational nicotine use is evolving, and with the increasing use of urine cotinine in the evaluation of nicotine exposure, further research is needed.

Translational research (TR) is the movement of fundamental scientific discoveries into healthcare settings and population health policy, and parallels the goals of DOHaD research. Unfortunately, there is little guidance on how to become a translational researcher. To understand the opinions of DOHaD trainees towards TR, we conducted a workshop at the DOHaD World Congress 2022. We found that trainees were enthusiastic for their work to have translational impact, and that they feel that holistic, multidisciplinary solutions may lead to more generalisable research. However, there lacks support for TR career pathways, which may stall the execution of the long-term vision of the DOHaD agenda. We put forward recommendations for trainees to clarify their purpose in pursuing TR and for seeking relevant people and patronages to support their training paths. For mentors, training institutions, and scientific societies, we recommend developing TR-specific programmes, and implementing training opportunities, networking events, and funding to support these endeavours.

Maternal psychosocial stress is associated with delivery of both small- and large-for-gestational-age newborns. Prior studies have relied on methods that do not capture fat mass (FM) vs. fat-free mass (FFM). We aimed to assess the relationship of maternal psychosocial stress, using the Edinburgh Postnatal Depression Scale (EPDS) and Cohen’s Perceived Stress Scale (PSS), with newborn body composition. The sample included 604 mother/newborn pairs in the Healthy Start study. We used linear regression to examine associations of EPDS (>6.5 vs. ≤6.5) and PSS (>21 vs. ≤21) with newborn adiposity (FM and %FM measured by air displacement plethysmography [ADP], BMI-for-age, weight-for-length, and weight-for-age z-scores) and lean mass (FFM and length-for-age z-score). Average age of the women was 29.2 ± 6 y. Fifty-five percent of the women were white, 26.2% Hispanic, and 12.1% Black. Twenty-four percent of women had EPDS >6.5 and 18.1% had PSS >21. Mean ± SD birthweight was 3136 ± 437 g. After adjustment for confounders, EPDS >6.5 vs. ≤6.5 corresponded with 35.3 (95% CI: 6.6, 64.0) g lower offspring FM and 0.18 (−0.03, 0.39) units shorter length z-score. PSS was not associated with any neonatal outcomes. Maternal psychosocial stress is associated with delivery of shorter newborns with less FM.

Late preterm (LP, born between 34 0/7 and 36 6/7 weeks of gestation) infants may experience several adverse outcomes, similar to those experienced by low birthweight (LBW, birthweight <2500 g) infants. However, while LP infants are often born with LBW, the association between LP and LBW remains unknown. This study aimed to investigate LBW rate and independent risk factors for LBW in LP singleton neonates. We retrospectively analyzed data of LP singleton neonates, born between 2013 and 2017, from the Japan Society of Obstetrics and Gynecology Successive Pregnancy Birth Registry System. The exclusion criteria included stillbirths and infants with missing data. Logistic regression analyses were performed to investigate maternal and perinatal factors associated with LBW in LP singletons. LBW was observed in 62.5% (n = 35,113) of 56,160 LP singleton births. In the multiple logistic regression analysis, LBW in LP neonates was independently associated with modifiable maternal factors, including pre-pregnancy underweight, inadequate gestational weight gain, and smoking during pregnancy, as well as non-modifiable factors, including younger maternal age, nulliparity, hypertensive disorder of pregnancy, preeclampsia, cesarean section delivery, and female offspring. According to the Japanese pregnancy birth registry data, more than half of LP neonates were LBW. We previously discussed the issue of LBW regarding infants with different backgrounds, as there are many different causes of LBW. Several risk factors should be subdivided and considered for the risk of LP and LBW.

The deleterious effects of adversity are likely intergenerational, such that one generation’s adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children’s behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

The maternal metabolic environment can be detrimental to the health of the offspring. In a previous work, we showed that maternal high-fat (HH) feeding in rabbit induced sex-dependent metabolic adaptation in the fetus and led to metabolic syndrome in adult offspring. As early development representing a critical window of susceptibility, in the present work we aimed to explore the effects of the HH diet on the oocyte, preimplantation embryo and its microenvironment. In oocytes from females on HH diet, transcriptomic analysis revealed a weak modification in the content of transcripts mainly involved in meiosis and translational control. The effect of maternal HH diet on the embryonic microenvironment was investigated by identifying the metabolite composition of uterine and embryonic fluids collected in vivo by biomicroscopy. Metabolomic analysis revealed differences in the HH uterine fluid surrounding the embryo, with increased pyruvate concentration. Within the blastocoelic fluid, metabolomic profiles showed decreased glucose and alanine concentrations. In addition, the blastocyst transcriptome showed under-expression of genes and pathways involved in lipid, glucose and amino acid transport and metabolism, most pronounced in female embryos. This work demonstrates that the maternal HH diet disrupts the in vivo composition of the embryonic microenvironment, where the presence of nutrients is increased. In contrast to this nutrient-rich environment, the embryo presents a decrease in nutrient sensing and metabolism suggesting a potential protective process. In addition, this work identifies a very early sex-specific response to the maternal HH diet, from the blastocyst stage.

The aim of this study was to evaluate whether high-fat (HF) diet intake during puberty can program obesity as well as generate glucose imbalance and hepatic metabolic dysfunctions in adult life. Male Wistar rats were randomly assigned into two groups: rats fed standard chow (NF) and rats fed a HF from postnatal 30-day-old (PND30) until PND60. Then, both groups were fed a standard chow from PND60 until PND120. Euthanasia and samples collections occurred at PND120. HF animals were overweight (+11%) and had increased adiposity, hyperphagia (+12%), hyperglycaemia (+13%), hyperinsulinemia (+69%), and hypertriglyceridemia (+34%). Plasma glucose levels during intravenous glucose tolerance test (ivGTT) and intraperitoneal insulin tolerance test (ipITT) were also higher in the HF group, whereas Kitt was significantly lower (–34%), suggesting reduced insulin sensitivity. In the same sense, HF animals present pancreatic islets hypertrophy and high β-cell mass. HF animals also had a significant increase in blood glucose levels during pyruvate tolerance test, indicating increased gluconeogenesis. Hepatic morphology analyses showed an increase in lipid inclusion in the HF group. Moreover, PEPCK and FAS protein expression were higher in the livers of the HF animals (+79% and + 37%, respectively). In conclusion, HF during puberty causes obese phenotype leading to glucose dyshomeostasis and nonalcoholic fatty liver disease, which can be related to the overexpression of proteins PEPCK and FAS.

An individual’s birthweight, a marker of in utero exposures, was recently associated with certain psychiatric conditions. However, studies investigating the relationship between an individual’s preterm birth status and/or birthweight and risk for depression during adulthood are sparse; we used data from the Women’s Health Initiative (WHI) to investigate these potential associations. At study entry, 86,925 postmenopausal women reported their birthweight by category (<6 lbs., 6–7 lbs. 15 oz., 8–9 lbs. 15 oz., or ≥10 lbs.) and their preterm birth status (full-term or ≥4 weeks premature). Women also completed the Burnham screen for depression and were asked to self-report if: (a) they had ever been diagnosed with depression, or (b) if they were taking antidepressant medications. Linear and logistic regression models were used to estimate unadjusted and adjusted effect estimates. Compared to those born weighing between 6 and 7 lbs. 15 oz., individuals born weighing <6 lbs. (βadj = 0.007, P < 0.0001) and ≥10 lbs. (βadj = 0.006, P = 0.02) had significantly higher Burnam scores. Individuals born weighing <6 lbs. were also more likely to have depression (adjOR 1.21, 95% CI 1.11–1.31). Individuals born preterm were also more likely to have depression (adjOR 1.18, 95% CI 1.02–1.35); while attenuated, this association remained in analyses limited to only those reportedly born weighing <6 lbs. Our research supports the role of early life exposures on health risks across the life course. Individuals born at low or high birthweights and those born preterm may benefit from early evaluation and long-term follow-up for the prevention and treatment of mental health outcomes.

The Developmental Origins of Health and Disease (DOHaD) approach supports that nutritional exposures in early life affect an individual’s later health and risk of disease. Dietary exposure during the preconception period may also influence individual, and inter- and transgenerational health and disease risk, in both men and women. This study aimed to describe knowledge of the DOHaD approach (DOHaDKNOWLEDGE) and diet quality in preconception young adults in Norway, to assess associations between DOHaDKNOWLEDGE and a Diet Quality Score (DQS), and to assess gender differences in those above. Data from 1362 preconception young adults was obtained from the PREPARED study baseline dataset. The sample had 88% women participants, a mean age of 27 years, 36% had overweight or obesity, and 77% had higher level of education. DOHaDKNOWLEDGE was assessed by the participants’ agreement to five statements using a Likert scale. Diet quality was assessed using aspects of diet quality and a DQS derived from a dietary screener. We found moderate level of both DOHaDKNOWLEDGE (12/20 points) and diet quality (DQS: 60/100 points), indicating potential for improvements. Specifically, the greatest potential for diet quality improvements were observed for sugary foods, red and processed meats, legumes, and unsalted nuts and seeds. Gender differences were observed for both DOHaDKNOWLEDGE and diet quality. DOHaDKNOWLEDGE was positively associated with DQS, adjusted for sociodemographic factors, with little evidence of an interaction effect by gender. This study indicates that knowledge of the DOHaD approach is positively associated with diet quality in preconception young men and women. Future studies should consider incorporating pregnancy intentions, relationship status, and health literacy.

Nonalcoholic fatty liver disease (NAFLD) involves changes in hepatic pathways, as lipogenesis, oxidative stress, endoplasmic reticulum (ER) stress, and macroautophagy. Maternal nicotine exposure exclusively during lactation leads to fatty liver (steatosis) only in the adult male offspring, not in females. Therefore, our hypothesis is that neonatal exposure to nicotine sex-dependently affects the signaling pathways involved in hepatic homeostasis of the offspring, explaining the hepatic lipid accumulation phenotype only in males. For this, between postnatal days 2 and 16, Wistar rat dams were implanted with osmotic minipumps, which released nicotine (NIC; 6 mg/Kg/day) or vehicle. The livers of offspring were evaluated at postnatal day 180. Only the male offspring that had been exposed to nicotine neonatally showed increased protein expression of markers of unfolded protein response (UPR), highlighting the presence of ER stress, as well as disruption of the activation of the macroautophagy repair pathway. These animals also had increased expression of diacylglycerol O-acyltransferase 1 and 4-hydroxynonenal, suggesting increased triglyceride esterification and oxidative stress. These parameters were not altered in the female offspring that had been neonatally exposed to nicotine, however they exhibited increased phospho adenosine monophosphate-activated protein kinase pAMPK expression, possibly as a protective mechanism. Thus, the disturbance in the hepatic homeostasis by UPR, macroautophagy, and oxidative stress modifications seem to be the molecular mechanisms underlying the liver steatosis in the adult male offspring of the nicotine-programming model. This highlights the importance of maternal smoking cessation during breastfeeding to decrease the risk of NAFLD development, especially in males.

Childhood infections have been shown to stunt growth, contribute to malnutrition and reduce cognition in early adulthood. This study aimed to assess relationships between early life infections and childhood cognition at age 11 years in the Newcastle Thousand Families Study (NTFS). The analysis included 741 members from the NTFS who had complete data for infections between birth and 5 years, and the 11-plus examinations. School records from the 11-plus examinations showed cognitive (IQ), English (EQ) and arithmetic (AQ) abilities. Housing conditions, overcrowding, birth order and social class were recorded at birth. Helicobacter pylori seropositivity was measured at age 49–51 years. Multivariable linear regression was used to examine relationships between infections and cognition. The total number of infections in the first 5 years of life was not significantly associated with IQ, EQ or AQ, nor were there significant relationships between cognitive outcomes and most infections. Tonsillitis did display a positive, significant association with IQ after adjustment for confounders (b = 6.43, 95% CI 0.92, 11.94, p = 0.022). Lower respiratory tract infections (LRTIs) showed significant negative relationships with all cognitive outcomes. H. pylori seropositivity at age 50 exhibited negative, significant relationships with EQ (p = 0.014) and AQ (p = 0.024) after adjustment for confounders. Although no significant relationship between overall infections and cognition were found, there were indications that LRTIs and gastrointestinal system infections may limit cognitive development. Given these infections remain prevalent, further research regarding severity and recurrence of infections and how they affect childhood cognition is needed.

Human height and related traits are highly complex, and extensively research has shown that these traits are determined by both genetic and environmental factors. Such factors may partially affect these traits through epigenetic programing. Epigenetic programing is dynamic and plays an important role in controlling gene expression and cell differentiation during (early) development. DNA methylation (DNAm) is the most commonly studied epigenetic feature. In this study we conducted an epigenome-wide DNAm association analysis on height-related traits in a Sub-Saharan African population, in order to detect DNAm biomarkers across four height-related traits. DNAm profiles were acquired in whole blood samples of 704 Ghanaians, sourced from the Research on Obesity and Diabetes among African Migrants study, using the Illumina Infinium HumanMethylation450 BeadChip. Linear models were fitted to detect differentially methylated positions (DMPs) and regions (DMRs) associated with height, leg-to-height ratio (LHR), leg length, and sitting height. No epigenome-wide significant DMPs were recorded. However we did observe among our top DMPs five informative probes associated with the height-related traits: cg26905768 (leg length), cg13268132 (leg length), cg19776793 (height), cg23072383 (LHR), and cg24625894 (sitting height). All five DMPs are annotated to genes whose functions were linked to bone cell regulation and development. DMR analysis identified overlapping DMRs within the gene body of HLA-DPB1 gene, and the HOXA gene cluster. In this first epigenome-wide association studies of these traits, our findings suggest DNAm associations with height-related heights, and might influence development and maintenance of these traits. Further studies are needed to replicate our findings, and to elucidate the molecular mechanism underlying human height-related traits.

Increasing evidence shows that maternal hyperglycemia inhibits cardiomyocyte (CM) proliferation and promotes cell apoptosis during fetal heart development, which leads to cardiac dysplasia. Accumulating evidence suggests that the overexpression of miR-21 in CMs has a protective role in cardiac function. Therefore, we investigated whether miR-21 can rescue CM injury caused by high glucose. First, we performed biological function analysis of miR-21-5p overexpression in H9c2 cells treated with high glucose. We found that the proliferation of H9c2 cells treated with high glucose decreased significantly and was rescued after overexpression of miR-21-5p. CCK-8 and EdU incorporation assays were performed to assess cell proliferation. The cell proliferation of the miR-21-5p mimic transfection group was improved compared with that of the NC mimic group (*p < 0.05, miR-21-5p mimics vs. NC mimics) when the proliferation of H9c2 cells was reduced by high glucose (****p < 0.0001, high glucose (HG) vs. normal glucose (NG)). Then, we verified the targeted and negative regulation of miR-21-5p on Rhob using a dual-luciferase activity assay and RT-qPCR, respectively. We further demonstrated that miR-21-5p regulates Rhob to rescue the inhibition of CM proliferation induced by high glucose. The CCK-8 results showed that the cell proliferation of the siRNA-Rhob group was higher than that of the NC mimic group (***p < 0.001) and that of the cotransfection group with Up-Rhob plasmids and miR-21-5p mimics was lower than that of the miR-21-5p mimic group (*p < 0.05). Conclusion: Overexpression of miR-21-5p rescues the inhibition of high glucose-induced CM proliferation through regulation of Rhob.

Low birthweight rats due to fetal undernutrition sustain higher corticosterone levels when exposed to stress. This is due to the upregulated expression of the pituitary-specific Gas5, a long noncoding RNA (lncRNA) that acts as a glucocorticoid receptor decoy and then competitively inhibiting the binding of glucocorticoids to DNA. However, the mechanism of Gas5 lncRNA upregulation remains unclear. Therefore, using the fetal undernourished model, we identified the factors that regulated Gas5 lncRNA expression and examined their effect on subsequent generations. We found that the expression levels of miR-23 was significantly lower in low birth-weight rats compared with controls. The expression of miR-23 was significantly lower and the expression levels of Gas5 lncRNA were significantly higher in the pituitary gland of low birth-weight offspring of the F2 and F3 generations compared with controls. The methyl modulator intervention in lactating F0 maternal rats restored miR-23 and Gas5 lncRNA expressions not only in F1, F2 and F3 offspring. Moreover, the intervention reduced circulating corticosterone levels and gene expressions in the pituitary gland after restraint stress exposure. In conclusion, miR-23-mediated alterations of the stress response are inherited and restored by methyl modulator intervention during lactation.