Programming the brain: common outcomes and gaps in knowledge from animal studies of IUGR

Available online 7 June 2016Abstract not availableDamien S. Hunter, Susan J. Hazel, Karen L. Kinda, Julie A. Owens, Julia B. Pitcher, Kathryn L. Gatfor

Maternal circadian rhythms and the programming of adult health and disease

The in utero environment is inherently rhythmic, with the fetus subjected to circadian changes in temperature, substrates and various maternal hormones. Meanwhile, the fetus is developing an endogenous circadian timing system, preparing for life in an external environment where light, food availability and other environmental factors change predictably and repeatedly every 24 hours. In humans, there are many situations that can disrupt circadian rhythms, including shift work, international travel, insomnias and circadian rhythm disorders (e.g., advanced/delayed sleep phase disorder), with a growing consensus that this chronodisruption can have deleterious consequences for an individual's health and wellbeing. However, the impact of chronodisruption during pregnancy on the health of both the mother and fetus is not well understood. In this review we outline circadian timing system ontogeny in mammals, and examine emerging research from animal models demonstrating long term negative implications for progeny health following maternal chronodisruption during pregnancy.Tamara J. Varcoe, X Kathryn L. Gatford, and David J. Kennawa

Variable maternal nutrition and growth hormone treatment in the second quarter of pregnancy in pigs alter semitendinosus muscle in adolescent progeny

Maternal nutrition and growth hormone (GH) treatment during early- to mid-pregnancy can each alter the subsequent growth and differentiation of muscle in progeny. We have investigated the effects of varying maternal nutrition and maternal treatment with porcine (p) GH during the second quarter of pregnancy in gilts on semitendinosus muscle cross-sectional area and fibre composition of progeny, and relationships between maternal and progeny measures and progeny muscularity. Fifty-three Large White×Landrace gilts, pregnant to Large White×Duroc boars, were fed either 2·2 kg (about 35 % ad libitum intake) or 3·0 kg commercial ration (13·5 MJ digestible energy, 150 g crude protein (N×6·25)/kg DM)/d and injected with 0, 4 or 8 mg pGH/d from day 25 to 50 of pregnancy, then all were fed 2·2 kg/d for the remainder of pregnancy. The higher maternal feed allowance from day 25 to 50 of pregnancy increased the densities of total and secondary fibres and the secondary:primary fibre ratio in semitendinosus muscles of their female progeny at 61 d of age postnatally. The densities of secondary and total muscle fibres in semitendinosus muscles of progeny were predicted by maternal weight before treatment and maternal plasma insulin-like growth factor-II during treatment. Maternal pGH treatment from day 25 to day 50 of pregnancy did not alter fibre densities, but increased the cross-sectional area of the semitendinosus muscle; this may be partially explained by increased maternal plasma glucose. Thus, maternal nutrition and pGH treatment during the second quarter of pregnancy in pigs independently alter muscle characteristics in progeny.Kathryn L. Gatford, Jason E. Ekert, Karina Blackmore, Miles J. De Blasio, Jodie M. Boyce, Julie A. Owens, Roger G. Campbell and Phillip C. Owen

Pre-birth origins of allergy and asthma

Abstract not availableK.L. Gatford, A.L. Wooldridge, K.L. Kind, R. Bischof, V.L. Clifto

Do I turn left or right? Effects of sex, age, experience and exit route on maze test performance in sheep

Abstract not availableDamien S. Hunter, Susan J. Hazel, Karen L. Kind, Hong Liu, Danila Marini, Julie A. Owens, Julia B. Pitcher, Kathryn L. Gatfor

Rapidly alternating photoperiods disrupt central and peripheral rhythmicity and decrease plasma glucose, but do not affect glucose tolerance or insulin secretion in sheep

Disrupting circadian rhythms in rodents perturbs glucose metabolism and increases adiposity. To determine whether these effects occur in a large diurnal animal, we assessed the impact of circadian rhythm disruption upon metabolic function in sheep. Adult ewes (n = 7) underwent 3 weeks of a control 12 h light-12 h dark photoperiod, followed by 4 weeks of rapidly alternating photoperiods (RAPs) whereby the time of light exposure was reversed twice each week. Measures of central (melatonin secretion and core body temperature) and peripheral rhythmicity (clock and metabolic gene expression in skeletal muscle) were obtained over 24 h in both conditions. Metabolic homeostasis was assessed by glucose tolerance tests and 24 h glucose and insulin profiles. Melatonin and core body temperature rhythms resynchronized within 2 days of the last photoperiod shift. High-amplitude Bmal1, Clock, Nr1d1, Cry2 and Per3 mRNA rhythms were apparent in skeletal muscle, which were phase advanced by up to 3.5 h at 2 days after the last phase shift, whereas Per1 expression was downregulated at this time. Pparα, Pgc1α and Nampt mRNA were constitutively expressed in both conditions. Nocturnal glucose concentrations were reduced following chronic phase shifts (zeitgeber time 0, -5.5%; zeitgeber time 12, -2.9%; and zeitgeber time 16, -5.7%), whereas plasma insulin, glucose tolerance and glucose-stimulated insulin secretion were not altered. These results demonstrate that clock gene expression within ovine skeletal muscle oscillates over 24 h and responds to changing photoperiods. However, metabolic genes which link circadian and metabolic clocks in rodents were arrhythmic in sheep. Differences may be due to the ruminant versus monogastric digestive organization in each species. Together, these results demonstrate that despite disruptions to central and peripheral rhythmicity following exposure to rapidly alternating photoperiods, there was minimal impact on glucose homeostasis in the sheep.Tamara J. Varcoe, Kathryn L. Gatford, Athena Voultsios, Mark D. Salkeld, Michael J. Boden, Leewen Rattanatray and David J. Kennawa

Placental and foetal growth restriction, size at birth and neonatal growth alter cognitive function and behaviour in sheep in an age- and sex-specific manner

OnLine Publication Sept 2015Intrauterine growth restriction and slow neonatal growth in humans are each associated with poorer learning, memory and cognitive flexibility in childhood and adulthood. The relative contributions of pre- and post-natal growth to cognitive outcomes are unclear, however. We therefore compared performance in learning, memory and reversal tasks using a modified Y-maze at 18 and 40weeks of age in offspring of placentally-restricted (PR: 10 M, 13 F) and control (23 M, 17 F) ovine pregnancies. We also investigated relationships between size at birth, neonatal growth rates and cognitive outcomes. PR had limited effects on cognitive outcomes, with PR males requiring more trials to solve the initial learning task than controls (P=0.037) but faster completion of reversal tasks in both sexes at 18weeks of age. In males, neonatal growth rate correlated inversely with numbers of trials and total time required to solve memory tasks at 40weeks of age. In females, bleat frequency in the first reversal task at 18weeks of age correlated positively with birth weight (r=0.734, P<0.05) and neonatal growth rate (r=0.563, P<0.05). We conclude that PR induces limited effects on cognitive outcomes in sheep, with some evidence of impaired learning in males, but little effect on memory or cognitive flexibility in either sex. Rapid neonatal growth predicted improved memory task performance in males, suggesting that strategies to optimize neonatal growth may have long-term cognitive benefits but that these may be sex-specific.Damien S. Hunter, Susan J. Hazel, Karen L. Kind, Hong Liu, Danila Marini, Lynne C. Giles, Miles J. De Blasio, Julie A. Owens, Julia B. Pitcher, Kathryn L. Gatfor

Circulating IGF1 and IGF2 and SNP genotypes in men and pregnant and non-pregnant women

Circulating IGFs are important regulators of prenatal and postnatal growth, and of metabolism and pregnancy, and change with sex, age and pregnancy. Single-nucleotide polymorphisms (SNPs) in genes coding for these hormones associate with circulating abundance of IGF1 and IGF2 in non-pregnant adults and children, but whether this occurs in pregnancy is unknown.We therefore investigated associations of plasma IGF1 and IGF2 with age and genotype at candidate SNPs previously associated with circulating IGF1, IGF2 or methylation of the INS–IGF2–H19 locus in men (nZ134), non-pregnant women (nZ74) and women at 15 weeks of gestation (nZ98). Plasma IGF1 concentrations decreased with age (P!0.001) and plasma IGF1 and IGF2 concentrations were lower in pregnant women than in non-pregnant women or men (each P!0.001). SNP genotypes in the INS–IGF2–H19 locus were associated with plasma IGF1 (IGF2 rs680, IGF2 rs1004446 and IGF2 rs3741204) and IGF2 (IGF2 rs1004446, IGF2 rs3741204 and H19 rs217727). In single SNP models, effects of IGF2 rs680 were similar between groups, with higher plasma IGF1 concentrations in individuals with the GG genotype when compared with GA (PZ0.016), or combined GA and AA genotypes (PZ0.003). SNPs in the IGF2 gene associated with IGF1 or IGF2 were in linkage disequilibrium, hence these associations could reflect other genotype variations within this region or be due to changes in INS–IGF2–H19 methylation previously associated with some of these variants. As IGF1 in early pregnancy promotes placental differentiation and function, lower IGF1 concentrations in pregnant women carrying IGF2 rs680 A alleles may affect placental development and/or risk of pregnancy complications.K L Gatford, G K Heinemann, S D Thompson, J V Zhang, S Buckberry, J A Owens, G A Dekker, C T Roberts and on behalf of the SCOPE Consortiu

Development of an experimental model of maternal allergic asthma during pregnancy

First published: 2 September 2015Maternal asthma during pregnancy adversely affects pregnancy outcomes but identification of the cause/s, and the ability to evaluate interventions, is limited by the lack of an appropriate animal model. We therefore aimed to characterise maternal lung and cardiovascular responses and fetal-placental growth and lung surfactant levels in a sheep model of allergic asthma. Immune and airway functions were studied in singleton-bearing ewes, either sensitised before pregnancy to house dust mite (HDM, allergic, n = 7) or non-allergic (control, n = 5), and subjected to repeated airway challenges with HDM (allergic group) or saline (control group) throughout gestation. Maternal lung, fetal and placental phenotypes were characterised at 140 ± 1 d gestational age (term, ∼147 d). The eosinophil influx into lungs was greater after HDM challenge in allergic ewes than after saline challenge in control ewes before mating and in late gestation. Airway resistance increased throughout pregnancy in allergic but not control ewes, consistent with increased airway smooth muscle in allergic ewes. Maternal allergic asthma decreased relative fetal weight (-12%) and altered placental phenotype to a more mature form. Expression of surfactant protein B mRNA was 48% lower in fetuses from allergic ewes than controls, with a similar trend for surfactant protein D. Thus, allergic asthma in pregnant sheep modifies placental phenotype, inhibits fetal growth and lung development consistent with observations from human pregnancies. Preconceptional allergen sensitisation and repeated airway challenges in pregnant sheep therefore provides an animal model to identify mechanisms of altered fetal development and adverse pregnancy outcomes caused by maternal asthma in pregnancy.Vicki L. Clifton, Timothy J.M. Moss, Amy L.Wooldridge, Kathryn L. Gatford, Bahar Liravi, Dasom Kim, Beverly S. Muhlhausler, Janna L. Morrison, Andrew Davies, Robert De Matteo, Megan J. Wallace, and Robert J. Bischo

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual\u27s risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig\u27s potential to enhance clinical therapeutic innovation to improve human health. (Figure presented.)