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

Abstract

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's 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's potential to enhance clinical therapeutic innovation to improve human health.

Keywords: DOHaD; animal models; fetus; guinea pig; placenta; pregnancy.

Figure 1. DOHaD studies have shown that exposures in one generation can have multigenerational and intergenerational effects

Changes in the grandmother (F0) or grandfather (F0) can influence the health of the granddaughter (F2) or son (F1), respectively. Transgenerational effects have also been identified that affect the great granddaughter (F3) and the grandson (F2). Adapted from Dickinson et al. (2016) with permission.

Figure 2. Structural similarities between guinea pig and human placenta

Reproduced with permission from Mess (2007).

Figure 3. Circulating progesterone remains elevated throughout pregnancy in guinea pigs and humans

Circulating progesterone (A) and corpus luteum (CL)‐dependence of pregnancy maintenance (B) reflect species differences in placental progesterone production throughout pregnancy. Bars indicate main source of circulating progesterone (white: CL, shaded: placenta). Ticks indicate that pregnancy can be maintained after removal of the ovary or CL, crosses indicate that either the CL or exogenous progesterone is required to maintain pregnancy. A is reproduced from Mitchell & Taggart (2009 with permission. Data in B are from Csapo & Pulkkinen (1978), Csapo et al. (1981), Al‐Gubory et al. (2000) and Bazer (2015).

Figure 4. Comparison of the stages of lung development in the human and guinea pig fetus

Figure 5. Ultrasound measurement of fetal size throughout gestation in the guinea pig

Images show measurement of abdominal circumference (AC, yellow lines) and biparietal diameter (BPD, green lines) from GD30 until term.

Figure 6. Immunostaining of matrix metalloproteinase 9 (MMP9) of normoxic (A and C) and 14 day hypoxic (B and D) fetal guinea pig hearts

Positive immunostaining (brown stain) for MMP9 was localized in both cardiac tissue and blood vessels. Negative controls were generated in the absence of the primary antibody to MMP9 protein (C and D). Sections were counterstained with haematoxylin QS (Vector Laboratories). Original magnification: ×200. From Oh et al. (2008b) with permission.

Figure 7. The authors