Foetal exposure to Panax ginseng extract reverts the effects of prenatal dexamethasone in the synthesis of testosterone by Leydig cells of the adult rat.

Epidemiological and experimental evidence suggest an association between an adverse prenatal environment and the predisposition to disease in adult life. This ‘foetal origins of disease’ hypothesis was first proposed by Barker and colleagues to explain the associations between low birth weight and increased risk of impaired glucose tolerance and cardiovascular disease (Barker 2004). The associations are thought to be consequence of permanent organizational effects (‘developmental programming’) on foetal physiology by a stimulus or insult during sensitive periods of development. Of these insults, foetal glucocorticoid (GC) overexposure is considered a powerful influence responsible for developmental programming of disease risk. During embryogenesis, GCs affect the normal structural development of organs and the programming of normal homoeostatic systems (Bertram & Hanson 2002; Fowden & Forhead 2004). However, exposure to excess GCs can permanently alter the structures and functions of the developing foetus (Harris & Seckl 2011). Dexamethasone (DEXA) is a synthetic glucocorticoid used on pregnant women at risk of preterm delivery due to its effectiveness in promoting foetal lung maturation (Matthews 2001). Despite this benefit, there is evidence that prenatal exposure to glucocorticoids has permanent cardiometabolic, neuroendocrine (overactive hypothalamic-pituitary-adrenal axis) and cognitive effects in adulthood in several species (Barker 1998; Seckl 2001; Matthews 2002). These adult manifestations are thought to be due to differences in the expression of the glucocorticoid receptor (GR) in the tissues (Levitt et al. 1996; Nyirenda et al. 1998; Cleasby et al. 2003), and DEXA is known to cause its effects by binding to the GR (Schaaf & Cidlowski 2002). Moreover, prenatal GC is known to programme reproductive health throughout the course of life (Davies & Norman 2002). In male rats, prenatal GC exposure affects reproductive development, including alterations in pubertal time and reductions in both the level of foetal intratesticular testosterone and anogenital distance (Holson et al. 1995; Davies & Norman 2002). However, evidence of the influence of GC exposure during development on adult testicular steroidogenesis is scarcer. For example, there is a report on the effect of prenatal exposure to DEXA on adult testicular steroidogenesis (Page et al. 2001), in which the authors describe an increase in testosterone production by adult rat Leydig cells, indicating that exposure to DEXA in utero can affect postnatal steroid synthesis. Panax ginseng is an herbal medicine frequently used as a general tonic or ‘adaptogen’ to fight stress in China, Japan and Korea for more than 200 years. Pharmacological effects of ginseng have been demonstrated in the central nervous system as well as the cardiovascular, immune and endocrine systems (Liu & Xiao 1992). Ginseng and its constituents have also demonstrated antidiabetes mellitus, anti-inflammatory, antitumour, antistress and anti-ageing properties (Liu & Xiao 1992; Yue et al. 2007; Lu et al. 2009). Regarding reproductive aspects, the administration of ginseng extract (GE) is reported to protect testicular function (Kim et al. 1999), induce spermatogenesis, enhance sperm survival rate, motility and quality (Salvati et al. 1996; Chen et al. 2001; Hwang et al. 2004; Park et al. 2006; Zhang et al. 2007; Yang et al. 2011) and to help preventing erectile dysfunction (Choi et al. 1999; Hwang et al. 2010) in human and animal models. Moreover, ginseng use is reported to exhibit no adverse effects on pregnancy outcomes (Holst et al. 2008; Seely et al. 2008; Shin et al. 2010). However, no data are available regarding the effects of ginseng on testicular steroidogenesis, and no attempt has been made to examine the effects of prenatal exposure to ginseng on postnatal testosterone production. On the other hand, research has demonstrated that ginsenosides, which are the major active components of ginseng, are functional ligands of GR (Lee et al. 1997), and it is generally supposed that most of the effects of ginsenosides on cells are mediated via GR. The aim of this study was to determine whether maternal exposure to GE can reverse the prenatal DEXA-induced increase in testosterone production by Leydig cells in adult rats. Ultrastructural and immunocytochemical analyses of Leydig cells were performed to assess cell integrity and the expression of two key proteins involved in androgen biosynthesis (StAR and P450scc), as well as the expression of GR, through which DEXA affects androgen biosynthesis.