Altered health outcomes in adult offspring of Sprague Dawley and Wistar rats undernourished during early or late pregnancy

Ellis-Hutchings, Robert G.; Zucker, Robert M.; Grey, Brian E.; Norwood, Joel; Richards, Judy H.; Lau, Christopher; Rogers, John M.

doi:10.1002/bdrb.20265

Cited by 13 publications

(15 citation statements)

References 45 publications

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“…Our post-weaning observations, outside the field of the present study, showed however that DEX rats remained permanently lighter than control rats, in line with a previous report [20], whereas UN rats recovered a normal b.w after 4–6 weeks of chow diet consumption without any hyperphagia (data not shown). The absence of early catch-up in our UN pups could be linked to 1) the stringency of prenatal maternal undernutrition used (moderate food restriction allows pups to recover normal b.w at weaning [31], [32] contrary to severe food restriction [8], [19]), 2) to poor nutrition provided by remaining underweight postpartum DEX and UN mothers nevertheless eating the same amount of food as CON and 3) to the strain of rats used (Sprague-Dawley rats exhibit a slightly delayed catch-up growth phase compared to Wistar rats [33]). …”

Section: Discussionmentioning

confidence: 99%

Early Metabolic Defects in Dexamethasone-Exposed and Undernourished Intrauterine Growth Restricted Rats

et al. 2012

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Poor fetal growth, also known as intrauterine growth restriction (IUGR), is a worldwide health concern. IUGR is commonly associated with both an increased risk in perinatal mortality and a higher prevalence of developing chronic metabolic diseases later in life. Obesity, type 2 diabetes or metabolic syndrome could result from noxious “metabolic programming.” In order to better understand early alterations involved in metabolic programming, we modeled IUGR rat pups through either prenatal exposure to synthetic glucocorticoid (dams infused with dexamethasone 100 µg/kg/day, DEX) or prenatal undernutrition (dams feeding restricted to 30% of ad libitum intake, UN). Physiological (glucose and insulin tolerance), morphometric (automated tissue image analysis) and transcriptomic (quantitative PCR) approaches were combined during early life of these IUGR pups with a special focus on their endocrine pancreas and adipose tissue development. In the absence of catch-up growth before weaning, DEX and UN IUGR pups both presented basal hyperglycaemia, decreased glucose tolerance, and pancreatic islet atrophy. Other early metabolic defects were model-specific: DEX pups presented decreased insulin sensitivity whereas UN pups exhibited lowered glucose-induced insulin secretion and more marked alterations in gene expression of pancreatic islet and adipose tissue development regulators. In conclusion, these results show that before any catch-up growth, IUGR rats present early physiologic, morphologic and transcriptomic defects, which can be considered as initial mechanistic basis of metabolic programming.

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Section: Discussionmentioning

confidence: 99%

Early Metabolic Defects in Dexamethasone-Exposed and Undernourished Intrauterine Growth Restricted Rats

et al. 2012

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“…If a particular fetus has fewer ossified bones or bones with less ossification (judged by radiography or intensity of staining with bone‐specific dyes) than is typically seen in control animals at the time of euthanasia, that fetus is considered to have experienced a reduced rate of development (Carney & Kimmel, ; Khera, ). Observations of reduced ossification are not malformations, because they are transient and typically catch up during the lactation period, which is a period of rapid growth during which rodent/rabbit offspring increase their body mass by 9–10 fold (Ellis‐Hutchings et al, ). This increase in body mass is accompanied by a proportional increase in the size of the bones.…”

Section: Embryology Of the Skeletonmentioning

confidence: 99%

Bone development in laboratory mammals used in developmental toxicity studies

DeSesso

2018

Birth Defects Research

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Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings. K E Y W O R D Sembryology, developmental toxicity testing, embryofetal toxicology testing, ossification, skeletal development, supernumerary ribs, wavy ribs | DEFINITION OF THE PROBLEMDevelopmental toxicity testing includes assessment of the near-term fetal skeleton in laboratory animals, particularly rats, mice, and rabbits. Alterations associated with treatment usually are categorized as malformations or variations, defined in section 2, below. The distinction between variations and malformations is not always clear, and different laboratories may produce different assessments. The biological importance of variations may also be unclear. We will review the published data on these skeletal findings with emphasis on the biological significance of the skeletal changes that have been the most variably interpreted.We are not the first authors to undertake an assessment of developmental changes in the skeleton. Among the helpful reviews in the literature are those by Kimmel and Wilson (1973), Chernoff and Rogers (2004), Tyl, Chernoff, and Rogers (2007), Daston and Seed (2007), Carney and Kimmel (2007), Beyer et al. (2011), Kimmel, Garry, andDeSesso (2014), and Hofmann, Buesen, Schneider, and van Ravenzwaay (2016). | REGULATORY REQUIREMENTS | TechniquesMost pharmaceutical and many non-pharmaceutical chemicals are evaluated for developmental toxicity in experimental animals prior to marketing approval. The requirements for pharmaceutical chemicals have been harmonized for use in Europe, the US, and Japan (ICH, 2005(ICH, , 2017 wileyonlinelibrary.com/journal/bdr2 1157 examination of preferably all fetuses is part of the developmental toxicity evaluation; however, the method of skeletal examination is not specified. The newer techniques of microcomputerized tomography and magnetic resonance imaging ...

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“…This may explain why, in the present study, there was no difference in fetal development (birth weight) at Day 90 of gestation, and consequently no catch-up growth was detected. However, the same level of undernutrition imposed during different windows of gestation may result in different effects on offspring [51].…”

Section: Undernutrition and Fetal Development In Cowsmentioning

confidence: 99%

Maternal Undernutrition in Cows Impairs Ovarian and Cardiovascular Systems in Their Offspring1

Mossa

Carter

Walsh

et al. 2013

Biology of Reproduction

160

135

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Severe prenatal undernutrition is usually associated with low birth weights in offspring and disorders including hypertension, obesity, and diabetes. Whether alterations in maternal nutrition insufficient to impair birth weight or prenatal growth impact the cardiovascular, stress, or metabolic systems is unknown. In addition, little is known about the effects of maternal dietary restriction on development of the reproductive system in mammals. Here, we use the bovine model, which has a gestational length and birth rate similar to humans, to show that offspring from nutritionally restricted dams (during the first trimester) were born with identical birth weights and had similar postnatal growth rates (to 95 wk of age), puberty, glucose metabolism, and responses to stress compared to offspring from control mothers. However, an increase in maternal testosterone concentrations was detected during dietary restriction, and these dams had offspring with a diminished ovarian reserve (as assessed by a reduction in antral follicle count, reduced concentrations of anti-Müllerian hormone, and increased follicle-stimulating hormone concentrations), enlarged aorta, and increased arterial blood pressure compared with controls. Our study links transient maternal undernutrition and enhanced maternal androgen production with a diminished ovarian reserve as well as potential suboptimal fertility, enlarged aortic trunk size, and enhanced blood pressure independent of alterations in birth weight, postnatal growth, or stress response and glucose tolerance. The implications are that relatively mild transient reductions in maternal nutrition during the first trimester of pregnancy (even those that do not affect gross development) should be avoided to ensure healthy development of reproductive and cardiovascular systems in offspring.

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Altered health outcomes in adult offspring of Sprague Dawley and Wistar rats undernourished during early or late pregnancy

Abstract: The most consistent effect of maternal undernutrition was elevated BP in offspring. Long-term health effects occurred with undernutrition during either window, but the UN10-21 period resulted in lower birth weight and more severe adult health effects.

Cited by 13 publications

References 45 publications

Early Metabolic Defects in Dexamethasone-Exposed and Undernourished Intrauterine Growth Restricted Rats

Early Metabolic Defects in Dexamethasone-Exposed and Undernourished Intrauterine Growth Restricted Rats

Bone development in laboratory mammals used in developmental toxicity studies

Maternal Undernutrition in Cows Impairs Ovarian and Cardiovascular Systems in Their Offspring1

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