Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

Maternal obesity (MO) during pregnancy and lactation leads to maternal and offspring metabolic dysfunction. Recent research has suggested that probiotics might be a novel approach to counteract these unwanted MO effects. The aim of this research was to analyze the impact of Leuconostoc SD23, a probiotic isolated from aguamiel (traditional Mexican drink), on MO metabolism in rats at the end of lactation (21 days). From weaning through lactation, control female Wistar rats (C) ate chow (5% fat) or high-energy obesogenic diet (MO; 25% fat). Half the C and MO mothers received a daily dose (1 × 1010 CFU/ml) of probiotic orally, control with probiotic (CP) and MO with probiotic (MOP), 1 month before mating and through pregnancy and lactation. Histological analyses of the liver, white adipose tissue and small intestine, body composition, glucose, insulin, triglycerides, and leptin were determined in mothers at the end of lactation. Maternal weight during pregnancy was greater in MO than C mothers, but similar at the end of lactation. Probiotic intervention had no effect on maternal weight. However, at the end of lactation, percentage of body fat was higher in MO than C, CP, and MOP. Serum glucose, homeostasis model assessment of insulin resistance, and triglycerides were higher in MO versus C, CP, and MOP. MO small intestine villus height was higher versus MOP, C, and CP. Leuconostoc SD23 did not present adverse effects in C. Conclusions: maternal administration of Leuconostoc SD23 has beneficial effects on maternal metabolism, which holds possibilities for preventing adverse offspring metabolic programming.

Early-life environmental and nutritional exposures are considered to contribute to the differences in cardiovascular disease (CVD) burden. Among sub-Saharan African populations, the association between markers of early-life exposures such as leg length and sitting height and CVD risk is yet to be investigated. This study assessed the association between leg length, sitting height, and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk among Ghanaian-born populations in Europe and Ghana. We constructed sex-specific quintiles for sitting height and leg length for 3250 participants aged 40–70 years (mean age 52 years; men 39.6%; women 60.4%) in the cross-sectional multicenter Research on Diabetes and Obesity among African Migrants study. Ten-year risk of ASCVD was estimated using the Pooled Cohort Equations; risk ≥7.5% was defined as “elevated” CVD risk. Prevalence ratios (PR) were estimated to determine the associations between sitting height, leg length, and estimated 10-year ASCVD risk. For both men and women, mean sitting height and leg length were highest in Europe and lowest in rural Ghana. Sitting height was inversely associated with 10-year ASCVD risk among all women (PR for 1 standard deviation increase of sitting height: 0.75; 95% confidence interval: 0.67, 0.85). Among men, an inverse association between sitting height and 10-year ASCVD risk was significant on adjustment for study site, adult, and parental education but attenuated when further adjusted for height. No association was found between leg length and estimated 10-year ASCVD risk. Early-life and childhood exposures that influence sitting height could be the important determinants of ASCVD risk in this adult population.

Intergenerational links of chronic disease have been suggested, as birthweight (BW) is associated with cardiovascular disease (CVD) and type 2 diabetes (T2D) in both parents and grandparents. However, most studies investigating these relationships have used relatively homogenous, white, majority populations. This study aimed to investigate the association between BW and CVD and T2D in a multiethnic population, that is, where the parents and grandparents often developed in a different environment from that where the child was born. Participants were women from a population-based cohort study of pregnant women (STORK Groruddalen), attending Child Health Clinics for antenatal care in three administrative city districts in Oslo, Norway, 2008–2010. Information about socioeconomic and lifestyle factors were collected among mothers and fathers. Parents reported history of CVD or T2D among grandparents. In logistic regressions, higher BW z-scores were associated with lower odds of T2D among maternal (OR 0.71 (95% CI 0.53, 0.97) and paternal (0.68 (0.49, 0.94) grandmothers after adjustments for parental and grandmothers’ characteristics. BW was not associated with CVD, but the association in maternal grandfathers was borderline significant. Our results indicate intergenerational transmission of chronic diseases like T2D in a multiethnic population.

Epidemiological studies have demonstrated an increased risk of developing non-transmittable diseases in adults subjected to adverse early developmental conditions. Metabolic and cardiovascular diseases have been the focus of most studies. Nevertheless, data from animal models also suggest early programming of fertility. In humans, it is difficult to assess the impact of the in utero environment retrospectively. Birthweight is commonly used as an indirect indicator of intrauterine development. This research is part of the ALIFERT study. We investigated a potential link between ponderal index at birth and female fertility in adulthood. Data from 51 infertile and 74 fertile women were analysed. BW was on average higher in infertile women, whereas birth length did not differ between the two groups; thus, resulting in a significantly higher ponderal index at birth in infertile women. Ponderal index at birth has been identified as a risk factor for infertility. These results suggest the importance of the intra-uterine environment, not only for long-term metabolic health but also for fertility.

Polycyclic aromatic hydrocarbons (PAHs) may contribute to obesity. Childhood obesity is a strong predictor of adult obesity and morbidity; however, the relationship between PAHs and obesity in young children (e.g., aged 3–5) has not been studied. We examined the association between urinary PAH metabolites and measures of obesity in children. We analyzed data from 3667 children aged 3–18 years who participated in the Canadian Health Measures Survey (CHMS, 2009–2015). We ran separate multivariable linear models to estimate the association between quartiles of PAH metabolites and each of body mass index (BMI) percentile, waist circumference (WC), and waist-to-height ratio (WHtR) in the total population, as well as in the age subgroups 3–5, 6–11, and 12–18, adjusting for age, sex, ethnicity, education, income quintile, diet, creatinine, and exposure to environmental tobacco smoke. A multinomial logistic regression model estimated adjusted odds ratios for risk of central obesity. BMI, WC, and WHtR were positively associated with total PAH and naphthalene metabolites in the total population aged 3–18 and in age groups 6–11 and 12–18. In 3–5 year olds, WHtR, but not BMI, was significantly associated with total PAH, naphthalene, and phenanthrene metabolites. Overall, those in the highest quartile for naphthalene or total PAH metabolites had three times greater odds of having central obesity compared with those in the lowest quartile. Urinary PAH metabolites are associated with WHtR, an indicator of central obesity and predictor of health risks associated with obesity, in children as young as 3–5.

The mental health of adult extremely low birth weight (ELBW) (<1000 g) survivors is poorer than their normal birth weight (NBW) peers. An understanding of the modifiable factors that affect this risk could provide targets for intervention. We set out to determine the extent to which a maternal history of mental health problems influenced mental health in ELBW and NBW offspring in adulthood. A total of 85 ELBW and 88 NBW individuals born between 1977 and 1982 in central west Ontario, Canada self-reported on internalizing (depression, anxiety) and externalizing (attention-deficit hyperactivity and antisocial) problems using the Diagnostic and Statistical Manual of Mental Disorders (DSM) scales of the Young Adult Self-Report at ages 22–26 and 30–35. They also reported on their mother’s maternal mental health using the Family History Screen. An interaction was found between birth weight status and maternal history of an anxiety disorder such that ELBW survivors showed a greater increase in internalizing scores than NBW participants at 22–26 (β = 10.27, p = 0.002) and at 30–35 years of age (β = 12.65, p = 0.002). An interaction was also observed between birth weight and maternal history of mood disorder, with higher externalizing scores in ELBW survivors than NBW adults at 22–26 (β = 7.21, p < 0.0001). ELBW adults appear to be more susceptible to the adverse mental health effects of exposure to maternal mood and anxiety disorders than those born at NBW. These links further highlight the importance of detecting and treating mental health problems in the parents of preterm survivors as a means of attempting to reduce the burden of psychopathology in this population.

Pregnant individuals who overeat are more likely to predispose their fetus to the development of metabolic disorders in adulthood. Physical training is a prevention and treatment interventional strategy that could treat these disorders, since it improves metabolism and body composition. This study assessed the protective effect of physical exercise against possible metabolic changes in generations F1 and F2, whose mothers were subjected to a high-sugar/high-fat (HS/HF) diet. Wistar rats belonging to generation F0 were distributed into four groups (n = 10): sedentary control (CSed), exercised control (CExe), sedentary HS/HF diet (DHSed) and exercised HS/HF diet (DHExe). From 21 to 120 days of age, maintained during pregnancy and lactation period, CSed/CExe animals received standard feed and DHSed/DHExe animals a HS/HF diet. Animals from the CExe/DHExe underwent physical training from 21 to 120 days of age. Male and female F1 and F2 received a normocaloric feed and did not perform any physical training, categorized into four groups (n = 10) according to the maternal group to which they belonged to. An increase in body weight, adiposity and glucose, and a change in lipid profile in F0 were observed, while exercise reduced the biochemical parameters comparing DHSed with DHExe. Maternal exercise had an effect on future generations, reducing adiposity, glucose and triglyceride concentrations, and preventing deleterious effects on glucose tolerance. Maternal overeating increased health risks both for mother and offspring, demonstrating that an HS/HF diet intake promotes metabolic alterations in the offspring. Importantly, the physical training performed by F0 proved to be protective against such effects.

The reported associations between birth weight and childhood cardiovascular disease (CVD) risk factors have been inconsistent. In this study, we investigated the relationship between birth weight and CVD risk factors at 11 years of age. This study used longitudinally linked data from three cross-sectional datasets (N = 22,136) in West Virginia; analysis was restricted to children born full-term (N = 19,583). The outcome variables included resting blood pressure [systolic blood pressure (SBP), diastolic blood pressure (DBP)] and lipid profile [total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL, and triglycerides (TG)]. Multiple regression analyses were performed, adjusting for child’s body mass index (BMI), sociodemographics, and lifestyle characteristics. Unadjusted analyses showed a statistically significant association between birth weight and SBP, DBP, HDL, and TG. When adjusted for the child’s BMI, the association between birth weight and HDL [b = 0.14 (95% CI: 0.11, 0.18) mg/dl per 1000 g increase] and between birth weight and TG [b = –0.007 (–0.008, –0.005) mg/dl per 1000 g increase] remained statistically significant. In the fully adjusted model, low birth weight was associated with higher LDL, non-HDL, and TGs, and lower HDL levels. The child’s current BMI at 11 years of age partially (for HDL, non-HDL, and TG) and fully mediated (for SBP and DBP) the relationship between birth weight and select CVD risk factors. While effects were modest, these risk factors may persist and amplify with age, leading to potentially unfavorable consequences in later adulthood.

Extremely low birth weight (ELBW) survivors have higher rates of shyness, a risk factor for poorer outcomes across the life span. Due to advances in fetal and neonatal medicine, the first generation of ELBW survivors have survived to adulthood and become parents. However, no studies have investigated the transmission of their stress vulnerability to their offspring. We explored this phenomenon using a population-based cohort of ELBW survivors and normal birth weight (NBW) controls. Using data from three generations, we examined whether the shyness and parenting stress of ELBW and NBW participants (Generation 2) mediated the relation between the parenting style of their parents (Generation 1) and shyness in their offspring (Generation 3), and the extent to which exposure to perinatal adversity (Generation 2) moderated this mediating effect. We found that among ELBW survivors, parenting stress (in Generation 2) mediated the relation between overprotective parenting style in Generation 1 (grandparents) and child shyness in Generation 3. These findings suggest that perinatal adversity and stress may be transmitted to the next generation in humans, as reflected in their perceptions of their children as shy and socially anxious, a personality phenotype that may subsequently place their children at risk of later mental and physical health problems.

Iron deficiency is common in pregnant and lactating women and is associated with reduced cognitive development of the offspring. Since iron affects lipid metabolism, the availability of fatty acids, particularly the polyunsaturated fatty acids required for early neural development, was investigated in the offspring of female rats fed iron-deficient diets during gestation and lactation. Subsequent to the dams giving birth, one group of iron-deficient dams was recuperated by feeding an iron-replete diet. Dams and neonates were killed on postnatal days 1, 3 and 10, and the fatty acid composition of brain and stomach contents was assessed by gas chromatography. Changes in the fatty acid profile on day 3 became more pronounced on day 10 with a decrease in the proportion of saturated fatty acids and a compensatory increase in monounsaturated fatty acids. Long-chain polyunsaturated fatty acids in the n-6 family were reduced, but there was no change in the n-3 family. The fatty acid profiles of neonatal brain and stomach contents were similar, suggesting that the change in milk composition may be related to the changes in the neonatal brain. When the dams were fed an iron-sufficient diet at birth, the effects of iron deficiency on the fatty acid composition of lipids in both dam’s milk and neonates’ brains were reduced. This study showed an interaction between maternal iron status and fatty acid composition of the offspring’s brain and suggests that these effects can be reduced by iron repletion of the dam’s diet at birth.

The early-life origins of disease hypothesis has been applied to obesity research and modeled through overnutrition, usually with a high-fat diet (HFD). Since the obesity epidemic coincided with societal change in dietary fat consumption, rather than amount, manipulation of fatty acid (FA) profile is an under-investigated area of study. Additionally, the binding of FAs to nuclear receptors may have persistent intergenerational, extranutritive endocrinological effects that interact with the actions of reproductive steroids causing sex-dependent effects. To determine the role of FA type in the effects underlying maternal HFD, we fed wild-type C57BL6/J mating pairs, from preconception through lactation, a HFD with high saturated fat levels from coconut oil or high linoleic acid (LA) levels from vegetable oil. Male and female offspring body weight and food intake were measured weekly for 25 weeks. Assays for glucose metabolism, body composition, and calorimetry were performed at 25 weeks. Plasma metabolic peptides and liver mRNA were measured terminally. Obesity was primarily affected by adult rather than maternal diet in males, yet in females, maternal HFD potentiated the effects of adult HFD. Maternal HFD high in LA impaired glucose disposal in males weaned onto HFD and insulin sensitivity of females. Plasma leptin correlated with adiposity, but insulin and insulin receptor expression in the liver were altered by maternal LA in males. Our results suggest that maternal FA profile is most influential on offspring glucose metabolism and that adult diet is more important than maternal diet for obesity and other parameters of metabolic syndrome.

It is estimated that 80% of the world population trusts traditional medicine. A large number of Americans use infusions of Bocconia frutescens L. leaves to treat cough and gastrointestinal disorders. However, phytochemical studies reveal that this plant contains alkaloids and other potentially harmful substances. This study aimed to evaluate the teratogenic effects of B. frutescens L. in an experimental model. Pregnant Wistar rats were administered lyophilized B. frutescens L. extract at 300 mg/kg/day or vehicle by orogastric route during the organogenesis period (gestation days 7–13), and external and internal congenital malformations were analyzed on the progeny on gestational day 20. Bocconia frutescens L. produced a significant increase in the number of different malformations, relative to the control group. We conclude that the consumption of B. frutescens L. during pregnancy at a dose equivalent to that consumed by humans increases the risk of teratogenic effects.

In lifecourse studies that encompass the adolescent period, the assessment of pubertal status is important, but can be challenging. We aimed to identify current methods for pubertal assessment and assess their appropriateness for population-based research by combining a review of the literature with the views of experts in the field. We searched bibliographic databases, extracted data and assessed study quality to inform a workshop with 21 experts. Acceptability of different approaches was explored with a panel of ten adolescents. We screened 11,935 abstracts, assessed 157 articles and summarised results from 38 articles. Combining these with the opinions of experts, self-assessment was found to be a practical method for use in studies where agreement with the gold standard of clinical assessment by physical examination to within one Tanner stage was acceptable. Serial measures of height and foot size accurately indicated timing of the pubertal growth spurt and age at peak height velocity, and were seen as feasible within longitudinal studies. Hormonal and radiological methods did not offer a practical means of assessing pubertal status. Assessment of voice maturation was promising, but needed validation. Young people thought that self-assessment, foot size and voice assessments were acceptable, and preferred an assessor of the same sex for clinical assessment. This review thus informs researchers working in lifecourse and adolescent health, and identifies future directions in order to improve validity of the methods.

This study aimed to assess the association between maternal-isolated oligohydramnios (IO) and offspring long-term neurological complications. A population-based retrospective cohort study was conducted, including all births at a single tertiary medical center in Israel between the years 1991 and 2014. Multiple pregnancies and potential pregnancy complications associated with oligohydramnios were excluded. The computerized obstetrical database was linked with the computerized dataset of all pediatric hospitalizations of the same medical center. Evaluation of cumulative neurological-associated hospitalizations rate over time was compared using a Kaplan–Meier survival curve. The Weibull survival parametric model was conducted to assess the neurological-associated hospitalization risk in the presence of IO, while accounting for potential confounders. A total of 190,259 pregnancies were included in the study, of which 4063 (2.13%) pregnancies were complicated with IO. Total neurological-related hospitalizations were significantly more common in the IO group (3.7% in the IO group and 3.0% in the comparison group, p = 0.005). Pervasive developmental disorder, movement disorders, developmental disorders, and degenerative and demyelization disorders were all specific neurological diagnoses significantly more common in the exposed group. The survival curve demonstrated a significantly higher cumulative hospitalization rate in the exposed group (log-rank p = 0.001). Using a multivariate model adjusting for gestational age, maternal age, and labor induction, an independent association between IO and long-term neurological morbidity of the offspring was observed (adjusted hazard ratio 1.203; 95% CI 1.02–1.42). In summary, a significant association was found between pregnancies complicated by IO and long-term neurological morbidity of the offspring.

Maternal high-fat diet (HFD) alters hypothalamic programming and disrupts offspring energy homeostasis in rodents. We previously reported that the loss of ERα signaling partially blocks the effects of maternal HFD in female offspring fed a standard chow diet. In a companion study, we determined if the effects of maternal HFD were magnified by an adult obesogenic diet in our transgenic mouse models. Heterozygous ERα knockout (wild-type (WT)/KO) dams were fed a control breeder chow diet (25% fat) or a semipurified HFD (45% fat) 4 weeks prior to mating with heterozygous males (WT/KO or WT/ knockin) to produce WT, ERα KO, or ERα knockin/knockout (KIKO) (no estrogen response element (ERE) binding) female offspring, which were fed HFD for 20 weeks. Maternal HFD potentiated the effects of adult HFD on KIKO and KO body weight due to increased adiposity and decreased activity. Maternal HFD also produced KIKO females that exhibit KO-like insulin intolerance and impaired glucose homeostasis. Maternal HFD increased plasma interleukin 6 and monocyte chemoattractant protein 1 levels and G6pc and Pepck liver expression only in WT mice. Insulin and tumor necrosis factor α levels were higher in KO offspring from HFD-fed dams. Arcuate and liver expression of Esr1 was altered in KIKO and WT, respectively. These data suggest that loss of ERE-dependent ERα signaling, and not total ERα signaling, sensitizes females to the deleterious influence of maternal HFD on offspring energy and glucose potentially through the control of peripheral inflammation and hypothalamic and liver gene expression. Future studies will interrogate the tissue-specific mechanisms of maternal HFD programming through ERα signaling.