Factors Affecting the Induction of Porphyria in the Laboratory Rat. Biochemical and Photobiological Studies Using Diethyl 1,4-dihydro-2,4,6-trimethyl-pyridine-3,5-dicarboxylate (DDC) as a Porphyrogenic Agent*

Porphyria induced by the fluorochrome, diethyl 1,4-dihydro-2,4,6-trimethyl py-ridine-3,5-dicarboxylate (DDC) has been studied in laboratory rats and the factors determining the pattern of porphyrin excretion have been assessed. Definitive studies demonstrating specific photosensitivity of the skin in the porphyric rats have been carried out.It has been established that the magnitude of porphyrin excretion as well as the type of porphyric pattern is dosage dependent. Increased fecal protoporphyrin output can occur without other evidence of porphyria at a low dosage level. As the drug dosage is increased, fecal and urinary coproporphyrin and finally urinary uroporphyrin values are additionally increased. These changes in porphyrin output have been explained on the current theory that DDC inhibits the incorporation of protoporphyrin into heme and the production of heme compounds so that by a positive feedback mechanism ALA synthetase is activated and excess urinary copro and uroporphyrin excretion occurs.The collidine derivative was well tolerated by animals receiving a conventional rat diet ad libitum, but in animals on purified diets a state of chronic nutrient deprivation precipitated acute toxicity. Toxic symptoms, associated with DDC intake at a high dosage level, included constipation, icterus, oliguria and premature death.The primary hepatic lesion of DDC-induced porphyria consisted in biliary hyperplasia with a surrounding mononuclear infiltrate. Discrete aggregation of protoporphyrin within the bile ducts and in the periductal inflammatory cells was localized by polarization and fluorescence microscopy. At autopsy the animals exhibiting toxic symptoms showed massive hepatic necrosis and renal tubular damage

Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes

Background: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. Methods: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. Results: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. Conclusions: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. Funding: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust.</p

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Publisher Copyright: © 2022 The AuthorsBackground: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.Peer reviewe