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Abstract
Areola/nipple retention (NR) is an established biomarker for an anti-androgenic mode of action in rat toxicity studies. It is a mandatory measurement under several OECD test guidelines and is typically assessed in combination with anogenital distance (AGD). Both NR and AGD are considered retrospective biomarkers of insufficient androgen signaling during the masculinization programming window in male fetuses. However, there are still aspects concerning NR as a biomarker for endocrine disruption that remains to be clarified. For instance, can NR be regarded a permanent adverse effect? Is it a redundant measurement if AGD is assessed in the same study? Is NR equally sensitive and specific to anti-androgenic chemical substances as a shortening of male AGD? In this review we discuss these and other aspects concerning the use of NR as a biomarker in toxicity studies. We have collected available literature from rat toxicity studies that have reported on NR and synthesized the data in order to draw a clearer picture about the sensitivity and specificity of NR as an effect biomarker for an anti-androgenic mode of action, including comparisons to AGD measurements. We carefully conclude that NR and AGD in rats for the most part display similar sensitivity and specificity, but that there are clear exceptions which support the continued assessment of both endpoints in relevant reproductive toxicity studies. Available literature also support the view that NR in infant male rats signifies a high risk for permanent nipples in adulthood. Finally, the literature suggests that the mechanisms of action leading from a chemical stressor event to either NR or short AGD in male offspring are overlapping with respect to canonical androgen signaling, yet differ with respect to other mechanisms of action.
Highlights
Over the past few decades we have witnessed an increase in male reproductive disorders such as cryptorchidism and hypospadias in new-born boys, or infertility and testis cancers in young men (Diamanti-Kandarakis et al, 2009; Skakkebaek et al, 2016)
We provide an overview of how various chemical classes can cause nipple retention (NR) in male rat offspring and discuss the differences between NR and anogenital distance (AGD) as biomarkers for anti-androgenicity
Based on our literature review we identified 147 relevant reproductive toxicity studies in rats that have reported on the effects of various chemicals on NR in male offspring, as well as coreporting of AGD (Supplementary Table S1)
Summary
Over the past few decades we have witnessed an increase in male reproductive disorders such as cryptorchidism and hypospadias in new-born boys, or infertility and testis cancers in young men (Diamanti-Kandarakis et al, 2009; Skakkebaek et al, 2016). Under normal circumstances AGD is approximately twice as long in males as in females and this measure can be used to determine the sex of various animal species, including cats and rodents (Hotchkiss and Vandenbergh 2005), but decreased AGD can be used as a biomarker indicating that the male fetus is generally undermasculinized (Schwartz et al, 2019a) Another morphometric biomarker of fetal androgen action is areola/nipple retention, in this review referred to as nipple retention (NR). NR is associated with adverse effects such as hypospadias and cryptorchidism, decreased penile length and reduced seminal vesicle weight in rats (Bowman et al, 2003; Christiansen et al, 2008) Since this sexually dimorphic regression of the male nipples is occurring in rats, but not in humans, NR is not a useful biomarker in human epidemiological studies. Since disrupted androgen signaling is directly relevant for adverse male reproductive health effects in humans, NR is a relevant biomarker which can be used to identify anti-androgenic chemicals and an important endpoint to assess in rat toxicological studies that aim to predict endocrine disruption and adverse effects on human health
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