10.Christians, JK; Shergill, HK; Albert, AYK. (2021) Sex-dependent effects of prenatal food and protein restriction on offspring physiology in rats and mice: systematic review and meta-analyses.Biol. Sex Differ. 12 Sex-dependent effects of prenatal food and protein restriction on offspring physiology in rats and mice: systematic review and meta-analyses
Developmental origins; Developmental programming; Maternal nutrition; Malnutrition; Prenatal exposure
Background Males and females may experience different effects of early-life adversity on life-long health. One hypothesis is that male foetuses invest more in foetal growth and relatively less in placental growth, and that this makes them susceptible to poor nutrition in utero, particularly if nutrition is reduced part-way through gestation. Objectives Our objectives were to examine whether (1) food and/ or protein restriction in rats and mice has consistent sex-dependent effects, (2) sex-dependency differs between types of outcomes, and (3) males are more severely affected when restriction starts part-way through gestation. Data sources PubMed and Web of Science were searched to identify eligible studies. Study eligibility criteria Eligible studies described controlled experiments that restricted protein or food during gestation in rats or mice, examined physiological traits in offspring from manipulated pregnancies, and tested whether effects differed between males and females. Results Our search identified 292 articles, of which the full texts of 72 were assessed, and 65 were included for further synthesis. A majority (50) used Wistar or Sprague-Dawley rats and so these were the primary focus. Among studies in which maternal diet was restricted for the duration of gestation, no type of trait was consistently more severely affected in one particular sex, although blood pressure was generally increased in both sexes. Meta-analysis found no difference between sexes in the effect of protein restriction throughout gestation on blood pressure. Among studies restricting food in the latter half of gestation only, there were again few consistent sex-dependent effects, although three studies found blood pressure was increased in males only. Meta-analysis found that food restriction in the second half of gestation increased adult blood pressure in both sexes, with a significantly greater effect in males. Birthweight was consistently reduced in both sexes, a result confirmed by meta-analysis. Conclusions We found little support for the hypotheses that males are more affected by food and protein restriction, or that effects are particularly severe if nutrition is reduced part-way through gestation. However, less than half of the studies tested for sex by maternal diet interactions to identify sex-dependent effects. As a result, many reported sex-specific effects may be false positives. DOI PubMed
9. Rogowska, MD; Pena, UNV; Binning, N; Christians, JK. (2021) Recovery of the maternal skeleton after lactation is impaired by advanced maternal age but not by reduced IGF availability in the mouse.PLoS One 16 Recovery of the maternal skeleton after lactation is impaired by advanced maternal age but not by reduced IGF availability in the mouse
Background Lactation results in substantial maternal bone loss that is recovered following weaning. However, the mechanisms underlying this recovery, and in particular the role of insulin-like growth factor 1 (IGF-I), is not clear. Furthermore, there is little data regarding whether recovery is affected by advanced maternal age. Methods Using micro-computed tomography, we studied bone recovery following lactation in mice at 2, 5 and 7 months of age. We also investigated the effects of reduced IGF-I availability using mice lacking PAPP-A2, a protease of insulin-like growth factor binding protein 5 (IGFBP-5). Results In 2 month old mice, lactation affected femoral trabecular and cortical bone, but only cortical bone showed recovery 3 weeks after weaning. This recovery was not affected by deletion of the Pappa2 gene. The amount of trabecular bone was reduced in 5 and 7 month old mice, and was not further reduced by lactation. However, the recovery of cortical bone was impaired at 5 and 7 months compared with at 2 months. Conclusions Recovery of the maternal skeleton after lactation is impaired in moderately-aged mice compared with younger mice. Our results may be relevant to the long-term effects of breastfeeding on the maternal skeleton in humans, particularly given the increasing median maternal age at childbearing. DOI PubMed
8. Baltayeva, J; Konwar, C; Castellana, B; Mara, DL; Christians, JK; Beristain, AG. (2020) Obesogenic diet exposure alters uterine natural killer cell biology and impairs vasculature remodeling in mice.Biol. Reprod. 102: 63-75 Obesogenic diet exposure alters uterine natural killer cell biology and impairs vasculature remodeling in mice
pregnancy; natural killer cell; uterus; decidua; placenta; diet-induced obesity; spiral artery remodeling; high-fat/high-sucrose diet; gene expression; gene microarray
Prepregnancy obesity associates with adverse reproductive outcomes that impact maternal and fetal health. While obesity-driven mechanisms underlying adverse pregnancy outcomes remain unclear, local uterine immune cells are strong but poorly studied candidates. Uterine immune cells, particularly uterine natural killer cells (uNKs), play central roles in orchestrating developmental events in pregnancy. However, the effect of obesity on uNK biology is poorly understood. Using an obesogenic high-fat/high-sugar diet (HFD) mouse model, we set out to examine the effects of maternal obesity on uNK composition and establishment of the maternal-fetal interface. HFD exposure resulted in weight gain-dependent increases in systemic inflammation and rates of fetal resorption. While HFD did not affect total uNK frequencies, HFD exposure did lead to an increase in natural cytotoxicity receptor-1 expressing uNKs as well as overall uNK activity. Importantly, HFD-associated changes in uNK coincided with impairments in uterine artery remodeling in mid but not late pregnancy. Comparison of uNK mRNA transcripts from control and HFD mice identified HFD-directed changes in genes that play roles in promoting activity/cytotoxicity and vascular biology. Together, this work provides new insight into how obesity may impact uNK processes central to the establishment of the maternal-fetal interface in early and mid pregnancy. Moreover, these findings shed light on the cellular processes affected by maternal obesity that may relate to overall pregnancy health. Summary sentence High-fat diet promotes uterine NK cell activation in pregnancy and associates with impaired vascular remodeling within the uterus and drives altered uterine NK gene expression. DOI PubMed
7.Christians, JK; Lennie, KI; Wild, LK; Garcha, R. (2019) Effects of high-fat diets on fetal growth in rodents: a systematic review.Reprod. Biol. Endocrinol. 17: 39 Effects of high-fat diets on fetal growth in rodents: a systematic review
Developmental origins; Fetal growth; Maternal nutrition; Obesity
Background: Maternal nutrition during pregnancy has life-long consequences for offspring. However, the effects of maternal overnutrition and/ or obesity on fetal growth remain poorly understood, e.g., it is not clear why birthweight is increased in some obese pregnancies but not in others. Maternal obesity is frequently studied using rodents on high-fat diets, but effects on fetal growth are inconsistent The purpose of this review is to identify factors that contribute to reduced or increased fetal growth in rodent models of maternal overnutrition. Methods: We searched Web of Science and screened 2173 abstracts and 328 full texts for studies that fed mice or rats diets providing similar to 45% or similar to 60% calories from fat for 3 weeks or more prior to pregnancy. We identified 36 papers matching the search criteria that reported birthweight or fetal weight. Results: Studies that fed 45% fat diets to mice or 60% fat diets to rats generally did not show effects on fetal growth. Feeding a 45% fat diet to rats generally reduced birth and fetal weight. Feeding mice a 60% fat diet for 4-9 weeks prior to pregnancy tended to increase in fetal growth, whereas feeding this diet for a longer period tended to reduce fetal growth. Conclusions: The high-fat diets used most often with rodents do not closely match Western diets and frequently reduce fetal growth, which is not a typical feature of obese human pregnancies. Adoption of standard protocols that more accurately mimic effects on fetal growth observed in obese human pregnancies will improve translational impact in this field.Website DOI PubMed
5. Chin, EH; Schmidt, KL; Martel, KM; Wong, CK; Hamden, JE; Gibson, WT; Soma, KK; Christians, JK. (2017) A maternal high-fat, high-sucrose diet has sexspecific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice.PLoS One 12 A maternal high-fat, high-sucrose diet has sexspecific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice
Maternal overnutrition and obesity during pregnancy can have long-term effects on offspring physiology and behaviour. These developmental programming effects may be mediated by fetal exposure to glucocorticoids, which is regulated in part by placental 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 1 and 2. We tested whether a maternal high-fat, high-sucrose diet would alter expression of placental 11 beta-HSD1 and 2, thereby increasing fetal exposure to maternal glucocorticoids, with downstream effects on offspring physiology and behaviour. C57BL/6J mice were fed a high-fat, high-sucrose (HFHS) diet or a nutrient-matched low-fat, no-sucrose control diet prior to and during pregnancy and lactation. At day 17 of gestation, HFHS dams had similar to 20% lower circulating corticosterone levels than controls. Furthermore, there was a significant interaction between maternal diet and fetal sex for circulating corticosterone levels in the fetuses, whereby HFHS males tended to have higher corticosterone than control males, with no effect in female fetuses. However, placental 11 beta-HSD1 or 11 beta-HSD2 expression did not differ between diets or show an interaction between diet and sex. To assess potential long-term consequences of this sex-specific effect on fetal corticosterone, we studied locomotor activity and metabolic traits in adult offspring. Despite a sex-specific effect of maternal diet on fetal glucocorticoids, there was little evidence of sex-specific effects on offspring physiology or behaviour, although HFHS offspring of both sexes had higher circulating corticosterone at 9 weeks of age. Our results suggest the existence of as yet unknown mechanisms that mitigate the effects of altered glucocorticoid exposure early in development, making offspring resilient to the potentially negative effects of a HFHS maternal diet. DOI
3. Crosley, EJ; Elliot, MG; Christians, JK; Crespi, BJ. (2013) Placental invasion, preeclampsia risk and adaptive molecular evolution at the origin of the great apes: Evidence from genome-wide analyses.Placenta 34: 127-132 Placental invasion, preeclampsia risk and adaptive molecular evolution at the origin of the great apes: Evidence from genome-wide analyses
DEEP TROPHOBLAST INVASION; MATRIX-METALLOPROTEINASES; NONHUMAN-PRIMATES; INSULIN-RECEPTORS; LOWLAND GORILLA; GENE-EXPRESSION; CELL INVASION; ACTIVIN-A; PREGNANCY; INHIBIN
Introduction: Recent evidence from chimpanzees and gorillas has raised doubts that preeclampsia is a uniquely human disease. The deep extravillous trophoblast (EVT) invasion and spiral artery remodeling that characterizes our placenta (and is abnormal in preeclampsia) is shared within great apes, setting Homininae apart from Hylobatidae and Old World Monkeys, which show much shallower trophoblast invasion and limited spiral artery remodeling. We hypothesize that the evolution of a more invasive placenta in the lineage ancestral to the great apes involved positive selection on genes crucial to EVT invasion and spiral artery remodeling. Furthermore, identification of placentally-expressed genes under selection in this lineage may identify novel genes involved in placental development. Methods: We tested for positive selection in approximately 18,000 genes using the ratio of non-synonymous to synonymous amino acid substitution for protein-coding DNA. DAVID Bioinformatics Resources identified biological processes enriched in positively selected genes, including processes related to EVT invasion and spiral artery remodeling. Results: Analyses revealed 295 and 264 genes under significant positive selection on the branches ancestral to Hominidae (Human, Chimp, Gorilla, Orangutan) and Homininae (Human, Chimp, Gorilla), respectively. Gene ontology analysis of these gene sets demonstrated significant enrichments for several functional gene clusters relevant to preeclampsia risk, and sets of placentally-expressed genes that have been linked with preeclampsia and/or trophoblast invasion in other studies. Conclusion: Our study represents a novel approach to the identification of candidate genes and amino acid residues involved in placental pathologies by implicating them in the evolution of highly-invasive placenta. (C) 2012 Elsevier Ltd. All rights reserved. DOI
2.Christians, JK; Hoeflich, A; Keightley, PD. (2006) PAPPA2, an enzyme that cleaves an insulin-like growth-factor-binding protein, is a candidate gene for a quantitative trait locus affecting body size in mice.Genetics 173: 1547-1553 PAPPA2, an enzyme that cleaves an insulin-like growth-factor-binding protein, is a candidate gene for a quantitative trait locus affecting body size in mice
Identifying genes responsible for quantitative variation remains a major challenge. We previously identified a quantitative trait locus (QTL) affecting body size that segregated between two inbred strains of mice. By fine mapping, we have refined the location of this QTL to a genomic region containing only four protein-coding genes. One of these genes, PAPPA2, is a strong candidate because it codes for an enzyme that cleaves insulin-like growth-factor-binding protein 5 (IGFBP-5), an important stimulator of bone formation. Among littermates that segregate only for the four-gene region, we show that the QTL has a significant effect on the circulating levels of IGFBP-5 and IGFBP-3 (the latter subject to limited degradation by PAPPA2), but not on levels of IGFBP-2 and IGFBP-4, which are not cleaved by PAPPA2. There are 14 nonsynonymous SNPs among QTL alleles, which may affect the activity of the translated protein. The refinement of the target region to four genes and the finding that the QTL affects IGFBP-5 levels suggest that PAPPA2 may be involved with normal postnatal growth. Our mapping results also illustrate the potentially fractal nature of QTL: as we mapped our QTL with increasing resolution, what appeared to be a single QTL resolved into three closely linked QTL (previous work), and then one of these was further dissected into two in this study.PDF
1. Oliver, F. , Christians, J.K. , Liu, X, Rhind, S., Verma, V., Davison, C., Brown, S.D.M, Denny, P., and Keightley, P.D. (2005) Regulatory variation at glypican-3 underlies a major growth QTL in mice.PLOS Biology 3: e135. Regulatory variation at glypican-3 underlies a major growth QTL in mice.
The genetic basis of variation in complex traits remains poorly understood, and few genes underlying variation have been identified. Previous work identified a quantitative trait locus (QTL) responsible for much of the response to selection on growth in mice, effecting a change in body mass of approximately 20%. By fine-mapping, we have resolved the location of this QTL to a 660-kb region containing only two genes of known function, Gpc3 and Gpc4, and two other putative genes of unknown function. There are no non-synonymous polymorphisms in any of these genes, indicating that the QTL affects gene regulation. Mice carrying the high-growth QTL allele have approximately 15% lower Gpc3 mRNA expression in kidney and liver, whereas expression differences at Gpc4 are non-significant. Expression profiles of the two other genes within the region are inconsistent with a factor responsible for a general effect on growth. Polymorphisms in the 3' untranslated region of Gpc3 are strong candidates for the causal sequence variation. Gpc3 loss-of-function mutations in humans and mice cause overgrowth and developmental abnormalities. However, no deleterious side-effects were detected in our mice, indicating that genes involved in Mendelian diseases also contribute to complex trait variation. Furthermore, these findings show that small changes in gene expression can have substantial phenotypic effects.PDF
