Foetal programming literature review

Summary

Results:

A comprehensive review of the literature was provided which offers a critical analysis of data pertaining to how foetal programming and epigenetics influence contemporary beef and sheep production traits. In places the review draws heavily on knowledge and experience gained from a wide variety of species but, in particular, rodents and humans where the majority of data resides.

The review is divided into 7 sections which provide detailed overviews of

the general field of developmental programing,
epigenetics and its role in long-term development,
programming of health and wellbeing,
programming of body composition,
programming of fertility,
impact of advanced reproductive technologies, and
industry relevance and recommendations.

General issues:

Research in this area currently follows three lines of enquiry: (i) investigations (mostly in rodents) into the mechanisms (including epigenetic) by which in utero environmental impacts arise, and whether these effects can be reversed; (ii) studies of the longer term consequences of various forms of prenatal insult (generally in humans and rodents) directed towards non-communicable diseases and offspring behaviour, and (iii) theoretical considerations relating to the evolutionary nature of these mechanisms. This review focuses on research concerning the first two of these issues.

Epigenetics:

Every cell within the body retains a copy of the entire genetic code (i.e. the whole genome) of the organism, although not all this information is utilised by every cell. Different cell types are ‘programmed’ to use the genetic code selectively to achieve their functions. This cell-type specific ‘programming’ is established during normal development and involves epigenetic mechanisms. Epigenetic processes allow gene expression patterns to differ between cells without alterations or mutations to the underlying DNA. Epigenetics can thus be described as: “the study of mitotically and/or meiotically heritable changes in gene function that are not explained by changes in DNA sequence”.

Stage of pregnancy:

In recent times cohort studies in humans have tended to focus on early gestation, including the peri-conceptional period, which is a time when the mammalian genome is most sensitive to epigenetic modifications. In studies with ruminants, moderately severe undernutrition up to 30 days after mating does not affect birth weight or growth rate but produces offspring that show symptoms of ‘metabolic syndrome’ (e.g. hypertension, insulin resistance). In some studies with sheep offspring also have behavioural disturbances and reduced survivability. In contrast, mild undernutrition during this period is associated with increased placental development and enhanced embryo survival. Poor nutrition in late gestation is reliably associated with reduced birth weights which, through impacts on offspring behaviour, thermoregulation and body reserves are associated with increased mortality. Shearing the housed pregnant ewe increases lamb birth weight by increasing dietary intakes, although improved lamb survival and post-natal growth rates are not always evident. The impact of gestational nutrition on calf weight has been less convincingly demonstrated. However, calf weight is reduced when cows experience either heat or cold stress which, in the case of heat stress, may be associated with reduced feed intakes. In addition, birth weight is reduced in cases where mothers experienced ill health (of various forms) during pregnancy.

Stress during pregnancy:

Pregnant farm animals may be exposed to many factors that can elicit physiological stress responses (e.g. transport, human contact, predators, housing). In pregnant rodents and humans these exposures are known to cause permanent and long lasting impacts on the developing offspring, particularly influencing behaviour, and stress reactivity. Very few studies have considered the impact of stress during pregnancy on offspring responses in cattle and sheep. In general, studies suggest that offspring behaviour is altered by exposure of the mother to stressful events, particularly if this occurs during early to mid-pregnancy; and that male offspring are more affected than females. Somewhat paradoxically, exposure to stress during late pregnancy may have positive impacts such as increasing offspring birth weight.

Immunity:

As the immune system develops largely in utero in farm livestock, immune function is likely to be susceptible to the effects of the maternal environment. In lambs the absorption of immunoglobulins from colostrum is affected by maternal intake of micronutrients (e.g. cobalt, vitamin E) as well as macronutrients (e.g. protein). A recent and largely unexplored concept in farm animals relates to the hologenome (i.e. the genome of the host plus all microorganisms associated with the host). In mammals microbial symbionts are vertically transmitted to offspring initially via the birth canal and subsequently from milk and the surrounding environment. In ruminants this is thought to affect the population of microbes that inhabit the rumen.

Muscle development and carcass composition: Muscle mass, is an important potential target for epigenetic mechanisms as, in cattle and sheep, the proliferation of muscle fibres occurs in utero. Lambs and calves are, therefore, born with a fixed number of muscle fibres, with subsequent growth occurring by hypertrophy (increase in fibre size). When nutritional insults on the pregnant ewe occur during early gestation then effects on muscle fibre number and type can be detected in young offspring, but these effects tend to be lost (or are too difficult to detect) in older sheep. Such studies, however, are few and offspring were often subsequently placed on high-planes of nutrition, which probably induced an element of compensation; although the nature of how such compensation may come about has not been explored.

Body fat, appetite and feed efficiency:

In humans and rodents, poor prenatal dietary intakes of energy, protein and micronutrients are associated with increased risk of adult obesity in offspring. In cattle and sheep there also appears to be some evidence of long-term programming of adiposity although, perhaps surprisingly, the development of adipose tissue in ruminants is less well understood than that of muscle. In sheep, nutritional restriction in early gestation, or low birth weight, is associated with increased adiposity, particularly in older (i.e. over 6 months) male offspring. Unlike muscle fibres, there is no evidence to suggest that the number of adipocytes (or precursor cells) is set at a specific stage of life.

Reproduction and fertility:

In female cattle and sheep, lifetime supply of potentially fertilizable oocytes (eggs) is established before birth and cannot be replenished thereafter. In males new spermatozoa are produced continually after puberty, but the number of Sertoli cells which are the primary determinant of sperm production and testes size in adult life is determined by proliferation during the foetal, neonatal and peripubertal periods. There certainly appears to be effects of malnutrition in utero on development of both male and female gonads. However, there is little evidence for an effect of prenatal nutrition on the onset of puberty in sheep or cattle, and the main impact appears to be on the number of ovarian follicles. There is some evidence of a reduction in ovulation rate and litter size in ewes malnourished during pregnancy, but larger scale studies are required to confirm these observations and their significance in commercial practice. Likewise in cattle, there is some evidence of effects of early pregnancy malnutrition on ovarian follicle reserve in offspring leading to poor subsequent fertility; but here the evidence is even more limited. There is also limited evidence for a negative impact of prenatal undernutrition on fertility of males, although very few long-term follow-up studies have been conducted in this area.

Environmental chemicals, including so called ‘endocrine disrupting compounds’ (EDCs) have the potential to programme various components of the reproductive axis (i.e. brain- pituitary-gonad-uterus) to malfunction in later life, and so affect fertility. There is certainly evidence in rodents to support such effects. Cattle and sheep grazing sewage-sludge treated pastures are exposed to higher than normal levels of such compounds, and so are potentially most at risk. To date the most worrying implication of EDC research relates to the high incidence of spermatogenic abnormalities in male offspring. Effects on female fertility are less evident.

Key take-home messages and recommendations include:

A. Nutrition during pregnancy: Adherence to existing standard dietary recommendations for macro- and micro-nutrients should avoid suboptimal in utero development that could have negative long-term effects on offspring growth and health. However, there is a lack of information for beef cattle and sheep to predict effects on carcass composition. EBLEX funded studies, therefore, could establish KPIs on commercial herds and flocks to validate/refine these recommendations, and to quantify the extent to which early life development may impact on long-term performance (both physical and financial performance). Data collection should include ewe/cow body condition at key stages of the annual production cycle and birth weight, ultimately with corresponding data on carcass yields. Another key trait to monitor is fertility across successive parities.

B. Gestational stress: This is an area that has been under investigated in both beef cattle and sheep. Evidence from rodent and human studies indicates that these effects are real. Factors such as housing, stocking density and handling during pregnancy are all worthy of further investigation.

C. Environmental chemicals: As around 73% of sewage sludge is dispensed on agricultural land, so there is a need to assess the effects that this may have on grazing livestock. The available evidence indicates effects on the development of male reproductive organs in sheep, but long-term consequences for ram fertility have not been properly ascertained; and effects in beef cattle have not been established. There is also the issue of bioaccumulation and, consequently, effects in humans consuming meat from animal grazing sludge-treated pastures.

D. Advanced breeding technologies: A watching brief on ‘Large Offspring Syndrome’ is recommended should activity in this area pick up again. These technologies have much to offer for livestock improvement, but the UK lags behind other countries, particularly those in North and South America. Improved standards of reproductive management (i.e. for sperm/egg/embryo donors and recipients) in both beef herds and sheep flocks are required. Improved handling facilities are needed as well as an improved awareness of factors that affect fertility. There is scope also to develop our understanding of why these technologies are so much more successful in Bos indicus and opposed to Bos taurine cattle. This extends to establishing a better understanding of their underlying fertility, which also differs between these two sub species.

Sector:

Beef & Lamb

Project code:

74402

Date:

01 August 2013 - 28 February 2014

Funders:

AHDB Beef & Lamb

AHDB sector cost:

£22,600

Total project value:

£22,600

Project leader:

University of Nottingham

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About this project

The Problem:

There is a growing body of evidence that both prenatal nutrition and other stresses can influence the performance of the resulting progeny in the long term. Currently few management strategies for beef and sheep production take these effects into account. Consequently, there is a need to understand the application and consequences of foetal programming for beef and sheep systems in England.

Aims and Objectives:

A comprehensive literature review is required to critically analyse the scientific literature on foetal programming and epigenetics in beef and sheep and consider how it relates and can be applied to English systems of production. This should cover:

The influence of maternal nutrition, health and other stresses during pregnancy on progeny performance, health, reproduction, behaviour, longevity and carcase quality
Intergenerational effects of foetal programming in primiparous heifers/ewes compared to multiparous cows/ewes
Mechanisms for foetal programming and epigenetic alterations to the genome of the developing foetus
Distillation of knowledge transfer messages relevant to English beef and sheep producers
Recommendations for future research needed to fill key knowledge gaps in relation to application of this science in English beef and sheep systems

Approach:

A written final report is required, which will be used by EBLEX staff to produce articles and other technical information. It will present the latest evidence in the context of commercial beef and sheep production and identify the areas where opportunities exist to improve system management to maximise the potential benefits foetal progamming could bring to English levy payers.