Recent advances in epigenetics have enhanced our knowledge of how environmental factors (UV radiation, drugs, infections, etc.) contribute to the development of autoimmune diseases (AID) in genetically predisposed individuals. Studies conducted in monozygotic twins discordant for AID and spontaneous autoimmune animal models have highlighted the importance of DNA methylation changes and histone modifications. Alterations in the epigenetic pattern seem to be cell specific, as CD4+ T cells and B cells are dysregulated in systemic lupus erythematosus, synovial fibroblasts in rheumatoid arthritis and cerebral cells in multiple sclerosis. With regard to lymphocytes, the control of tolerance is affected, leading to the development of autoreactive cells. Other epigenetic processes, such as the newly described miRNAs, and post-translational protein modifications may also be suspected. Altogether, a conceptual revolution is in progress, in AID, with potential new therapeutic strategies targeting epigenetic patterns.

Offspring of diabetic mothers experience an increased risk for type 2 diabetes but it is not known whether diabetic pregnancies also confer a higher inter-generational risk for diabetic complications. Because microalbuminuria is a sensitive indicator of glomerular damage, we compared the urine albumin:creatinine ratios (ACRs) between 65 infants of diabetic mothers (InfDM+) and 59 infants of non-diabetic mothers (InfDM−), and repeated the comparisons in 21 InfDM+ and 19 InfDM− when children were 5–19 months old. ACRs were higher among neonates compared with normal reference values for adults, but declined with increasing age. The only independent predictor of higher ACRs in a logistic regression model (⩾13 mg/mmol v. <13 mg/mmol) was the presence of delivery complications (odds ratio 2.95; P = 0.015). Neither high nor low birth weight was associated with higher neonatal ACRs. The most unique finding of the study was that InfDM+ had significantly lower ACRs than InfDM− [mean = 12.9 (median = 6.0) v. mean = 16.6 (median = 11.5), respectively at P = 0.05] even after adjusting for other variables using logistic regression (odds ratio 0.25; P = 0.001). In contrast, by 5–19 months, there was a trend toward higher ACRs among InfDM+ compared with InfDM− [mean = 6.3 mg/mmol (median = 1.9) v. mean = 3.0 mg/mmol (median = 2.5), respectively at P = 0.25]. Lower ACRs in InfDM+ may be due to developmental changes in fetal kidneys induced by hyperinsulinemia. Although the implications of this observation are unclear, it is possible that exposure to a diabetic intrauterine environment might influence the later risk for renal disease.

Osteoprotegerin (OPG) is involved in the regulation of bone turnover, but little is known about this protein during pregnancy or among neonates. We undertook a prospective longitudinal study to identify relationships between OPG, markers of bone turnover and birth outcomes in 155 pregnant adolescents (13–18 years) and their newborns. Maternal blood samples were collected at mid-gestation and at delivery. Cord blood was obtained at delivery. Serum OPG, estradiol and markers of bone formation (osteocalcin) and resorption (N-telopeptide) were assessed in all samples. Placental OPG expression was assessed in placental tissue obtained at delivery. Bone markers and OPG increased significantly from mid-gestation (26.0 ± 3.4 weeks) to delivery (39.3 ± 2.6 weeks). Neonatal OPG was significantly lower, but bone turnover markers were significantly higher than maternal values at mid-gestation and at parturition (P < 0.001). African-American adolescents had higher concentrations of OPG than Caucasian adolescents at mid-gestation (P = 0.01) and delivery (P = 0.04). Gestational age and estradiol were also predictors of maternal OPG at mid-gestation and delivery. OPG concentrations in cord blood were correlated with maternal OPG concentrations and were negatively associated with infant birth weight z-score (P = 0.02) and ponderal index (P = 0.02). In conclusion, maternal OPG concentrations increased across gestation and were significantly higher than neonatal OPG concentrations. Maternal and neonatal OPG concentrations were not associated with markers of bone turnover or placental OPG expression, but neonatal OPG was inversely associated with neonatal anthropometric measures. Additional research is needed to identify roles of OPG during pregnancy.

Birth weight for gestational age (BW/GA) has been associated with a risk of adverse health outcomes. Biological indices of pregnancy complications, maternal mid-pregnancy serum biomarkers and placental pathology may shed light on these associations, but at present, they are most often examined as single entities and offer little insight about overlap. In addition, these indices are typically assessed in relation to the extremes of the BW/GA distribution, leaving open the question of how they relate to the entire BW/GA distribution. Addressing issues such as these may help elucidate why postnatal health outcomes vary across the BW/GA continuum. In this study, we focused on a subset of women who participated in the Pregnancy Outcomes and Community Health Study (n = 1371). We examined BW/GA (i.e. gestational age and sex-referenced z-scores) in relation to obstetric complications, second trimester maternal serum screening results and histologic evidence of placental pathology along with maternal demographics, anthropometrics and substance use. In adjusted models, mean reductions in BW/GA z-scores were associated with preeclampsia (β = −0.70, 95% CI −1.04, −0.36), high maternal serum alpha fetoprotein (β = −0.28, 95% CI −0.43, −0.13), unconjugated estriol (β = −0.31/0.5 multiples of the median decrease, 95% CI −0.41, −0.21) and high levels of maternal obstructive vascular pathology in the placenta (β = −0.46, 95% CI −0.67, −0.25). The findings were similar when preterm infants, small-for-gestational age or large-for-gestational age infants were excluded. More research is needed to examine how the factors studied here might directly mediate or mark risk when evaluating the associations between BW/GA and postnatal health outcomes.

Rodents, particularly rats, are used in the majority of intrauterine growth restriction (IUGR) research. An important tool that is lacking in this field is the ability to impose IUGR on transgenic mice. We therefore developed a novel mouse model of chronic IUGR using U-46619, a thromboxane A2 (TXA2) analog, infusion. TXA2 overproduction is prevalent in human pregnancies complicated by cigarette smoking, diabetes mellitus and preeclampsia. In this model, U-46619 micro-osmotic pump infusion in the last week of C57BL/6J mouse gestation caused maternal hypertension. IUGR pups weighed 15% less, had lighter brain, lung, liver and kidney weights, but had similar nose-to-anus lengths compared with sham pups at birth. Metabolically, IUGR pups showed increased essential branched-chain amino acids. They were normoglycemic yet hypoinsulinemic. They showed decreased hepatic mRNA levels of total insulin-like growth factor-1 and its variants, but increased level of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha. IUGR offspring were growth restricted from birth (P1) through postnatal day 21 (P21). IUGR males caught up with sham males in weight by P28, whereas IUGR females caught up with sham females by P77. IUGR males surpassed sham males in weight by P238. In summary, we have a non-brain sparing IUGR mouse model that has a relative ease of surgical IUGR induction and exhibits features similar to the chronic IUGR offspring of humans and other animal models. As transgenic technology predominates in mice, this model now permits the imposition of IUGR on transgenic mice to interrogate mechanisms of fetal origins of adult disease.

Rat offspring born to dams fed a high multivitamin diet (HV) are shown to have increased risks of obesity and metabolic syndrome. We hypothesized that a low-vitamin postweaning diet would enhance these characteristics in offspring born to HV dams. During pregnancy, Wistar rats were fed the AIN-93G diet with or without a 10-fold increase in vitamin content. In Experiment 1, at weaning, males were fed the recommended diet (RV) or a diet with 1/3 the vitamin content (1/3 RV) for 12 weeks. In Experiment 2, males and females were fed the RV diet or 1/6 RV diet for 35 weeks. Body weight was measured on a weekly basis, food intake on a daily basis, and for 1 h after an overnight fast following glucose gavage at 6, 12 and 24 weeks. Blood glucose and insulin responses to an oral glucose load were measured at 30 weeks. Males from HV dams, compared with those from RV dams, gained more weight in Experiment 1 (+7%, P < 0.05) and Experiment 2 (+11%, P < 0.0001), along with higher glucose response (+33%, P < 0.05). The 1/6 RV pup diet led to lower weight gain in males (−16%, P < 0.0001) and females (−13%, P < 0.0005), and lower food intake in males (−9%, P < 0.01) independent of the gestational diet. Females on the 1/6 RV diet and from HV dams had higher 1 h food intake (+36%, P < 0.05) and lower insulin response (−25%, P < 0.05) compared with those from RV dams. Exposure of the offspring to low-vitamin diets did not amplify the expression of the metabolic syndrome observed in those born to dams fed an HV diet.