The results of different human epidemiological datasets provided the impetus to introduce the now commonly accepted theory coined as 'developmental programming', whereby the presence of a stressor during gestation predisposes the growing fetus to develop diseases, such as metabolic dysfunction in later postnatal life. However, in a clinical setting, human lifespan and inaccessibility to tissue for analysis are major limitations to study the molecular mechanisms governing developmental programming. Subsequently, studies using animal models have proved indispensable to the identification of key molecular pathways and epigenetic mechanisms that are dysregulated in metabolic organs of the fetus and adult programmed due to an adverse gestational environment. Rodents such as mice and rats are the most used experimental animals in the study of developmental programming. This review summarises the molecular pathways and epigenetic mechanisms influencing alterations in metabolic tissues of rodent offspring exposed to in utero stress and subsequently programmed for metabolic dysfunction. By comparing molecular mechanisms in a variety of rodent models of in utero stress, we hope to summarise common themes and pathways governing later metabolic dysfunction in the offspring whilst identifying reasons for incongruencies between models so to inform future work. With the continued use and refinement of such models of developmental programming, the scientific community may gain the knowledge required for the targeted treatment of metabolic diseases that have intrauterine origins.

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Background RNA is a critical analyte for unambiguous detection of actionable mutations used to guide treatment decisions in oncology. Currently available methods for gene fusion detection include molecular or antibody-based assays, which suffer from either being limited to single-gene targeting, lack of sensitivity, or long turnaround time. The sensitivity and predictive value of next generation sequencing DNA-based assays to detect fusions by sequencing intronic regions is variable, due to the extensive size of introns. The required depth of sequencing and input nucleic acid required can be prohibitive; in addition it is not certain that predicted gene fusions are actually expressed. Results Herein we describe a method based on pyrophosphorolysis to include detection of gene fusions from RNA, with identical assay steps and conditions to detect somatic mutations in DNA [1], permitting concurrent assessment of DNA and RNA in a single instrument run. Conclusion The limit of detection was under 6 molecules/ 6 µL target volume. The workflow and instrumentation required are akin to PCR assays, and the entire assay from extracted nucleic acid to sample analysis can be completed within a single day.

Maternal-offspring interactions in mammals are mainly characterised by cooperation, but also conflict. Over evolutionary time, the fetus has evolved to manipulate the mother's physiology to increase nutrient transfer through the placenta, but these mechanisms are poorly characterized. The imprinted Igf2 (insulin-like growth factor 2) gene is highly expressed in mouse placental cells with endocrine functions. Here, we show that in the mouse, deletion of Igf2 in these cells leads to impaired placental endocrine signalling to the mother, but remarkably does not result in changes in placental morphology, growth or size. Mechanistically, we find that Igf2 via defective production of hormones, including prolactins, is essential for the establishment of the insulin-resistance state during pregnancy, and the appropriate partitioning of nutrients to the developing fetus. Consequently, fetuses are growth restricted and hypoglycemic, due to impaired placental glucose transfer from the mother to the fetus. Furthermore, Igf2 loss from placental endocrine cells has long-lasting effects on offspring adiposity and glucose homeostasis in adult life. Our study provides long-sought compelling experimental evidence for an intrinsic fetal manipulation system, which operates in the placenta to modify maternal metabolism and resource allocation to the fetus, with consequences for offspring metabolic health in later life.