Content area
Full text
Introduction
Epidemiological studies support the view that maternal exposure to certain environmental chemicals with endocrine-disrupting potential may be associated with adverse effects on reproductive development of the resulting offspring, including androgen-dependent processes in males (Skakkebaek et al. 2016). More recently, experimental animal evidence suggests that in utero exposures to endocrine-disrupting chemicals could have intergenerational effects via epigenetic changes to fetal germ cells (Lane et al. 2015; Braun et al. 2017). In contrast with unintentional exposure to low levels of environmental chemicals, pregnant women may be intentionally exposed to relatively high doses of pharmaceuticals—if medications have reproductive developmental effects, and their use is associated with environmental exposures, they could confound associations between in utero environmental chemical exposures and developmental outcomes in human observational studies. In this context, data collected from pregnant women in the United States (Werler et al. 2005), France (Philippat et al. 2011), and Denmark (Jensen et al. 2010) during the late 1990s to mid-2000s indicated that the majority (55% in Denmark, 70–76% in the United States, 89% in France) used an analgesic at least once during pregnancy, with most (47–66%) reporting use of acetaminophen (paracetamol) and 5–15% reporting use of ibuprofen (a nonsteroidal anti-inflammatory drug; NSAID), both of which are available without medical prescription (Campbell et al. 2016; Werler et al. 2005). Acetaminophen and NSAIDS are able to cross the placenta into the fetal circulation and as a result have the potential to affect fetal development (Alano et al. 2001; Naga Rani et al. 1989; Nitsche et al. 2017; Weigand et al. 1984).
Epidemiological studies have reported some evidence of associations between analgesic use during pregnancy and cryptorchidism in sons, though findings have been inconsistent within and among different study populations (Berkowitz and Lapinski 1996; Jensen et al. 2010; Kristensen et al. 2011; Philippat et al. 2011; Snijder et al. 2012). Testicular descent is primarily under the influence of testosterone produced by the Leydig cells of the fetal testis, and experimental studies have shown that the analgesics, acetaminophen, ibuprofen, and aspirin can all reduce testosterone production by the fetal testis in the rat (Kristensen et al. 2011, 2012; van den Driesche et al. 2015). A recent study using a xenograft model of human fetal testis tissue collected between 14–20 gestational weeks reported that...