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Congenital cryptorchidism is the most common male reproductive disorders that is manifest at birth. It affects 2% to 9% of newborn boys (1) and the incidence have been reported to increase (2,3). Cryptorchidism confers an increased risk of infertility and testicular cancer in adulthood (3-5). The process of testis descent is dependent on hormones secreted by fetal testis. According to the studies using rat, fetal testosterone deficiency during a critical period in masculinization development leads to male reproductive disorders such as cryptorchidism (6-8). However, the environmental/lifestyle factors that reduce testosterone production have remained elusive, since it is not possible at present to decide whether rodent models mimic hormone secretion in human fetal testis.
Whether animal models can be used to predict human response to drugs and other chemicals is apparently a contentious issue. Recently, van den Driesche et al. proposed that chronic application of acetaminophen, a pain reliever and a fever reducer, attenuates testosterone production by human fetal testis using an original xenograft model (9). The xenograft model using human fetal testicular tissue can be a possible solution to translate experimental evaluation to clinical drug safety. Actually, some human studies mentioned an association between the use of acetaminophen in pregnant mothers and cryptorchidism in their sons.
Acetaminophen (N-acetyl-p-aminophenol, paracetamol) is a member of the aniline family of analgesics, which is widely available as over-the-counter drug. Because acetaminophen may be generally perceived as a safe drug, it is most commonly taken by pregnant women (1,10). Because acetaminophen is known to freely cross the placenta (2,11), the effects on fetus are needed to be considered for use during pregnancy. To date, several different birth cohort studies have associated maternal use of acetaminophen with increasing risk for reproductive disorders in male offspring (12-14).
Experimental investigation using rats revealed that intrauterine exposure to acetaminophen, with a lowest dose of 150 mg/kg/day, reduces the anogenital distance (AGD) (6), which is dependent on fetal exposure to testosterone in the male offspring (14). Also in ex vivo experiments based on the culture system of rat fetal testes (gestational day 14.5) for 1 to 3 days, acetaminophen directly inhibits testosterone production by the rat fetal testes (14,15). However, in the same ex vivo experiments using human fetal testis (7–12 weeks), testosterone production was unaffected by exposure to acetaminophen nor its metabolite N-(4-hydroxyphenyl)-arachidonoylethanolamide (AM404) at concentrations relevant to human therapeutic dose (16), although it remains unclear whether the contradiction reflects the differences of species or the differences existing in the culture systems.
Because it is impossible to investigate directly the effects on human fetal testis development for ethical reasons, the development of appropriate model is necessary for study of human fetal testis development. In this context, the xenograft model of human fetal testis was developed as a new approach to investigate human fetal testis development (17). Small pieces of human fetal testis xenografted under the dorsal skin of male castrated nude mice were maintained for 7 days. The xenografts showed more than 75% survival with normal morphology and produced testosterone when host mice were treated with human chorionic gonadotropin (hCG) to mimic human in utero environment. Using human fetal testes (14 to 20 weeks), van den Driesche et al. tried to evaluate the effect of exposure to acetaminophen on testosterone production (9). They tested three different doses and regimens: (I) a single high dose (350 mg/kg) of acetaminophen administered orally daily for 7 days; (II) a therapeutic dose (20 mg/kg) administered orally 3 times a day for 7 days; (III) a therapeutic dose (20 mg/kg) administered orally 3 times a day for a single day. They showed that 1 week’s exposure to acetaminophen, even a human-equivalent therapeutic regimen, results in reduced testosterone production by xenografted human fetal testis tissue, whilst short-term (1 day) use does not result in any long-lasting suppression of testosterone production.
We wonder how much impacts these results have on drug safety problem. The purpose of the test using animal models is to predict human response then the tests must be evaluated by how well it conforms to human response. The xenograft model in pseudo-human in utero environment (9) is applicable to improve predictability of reproductive potentials, which has a large impact on drug safety on chronic toxicity tests. At the same time, the authors used a rat model to confirm the difference between acute and chronic exposure of acetaminophen then to unravel the molecular mechanisms, because availability of human tissue is limited. Although the limitation exists, key experiments using the xenograft model must be a robust predictor of human response so far. It has not been determined whether the prediction would be also a potential guide for decision making in drug safety. Further work, especially with retrospective clinical studies, will be necessary to use the xenograft system as a guide for decision making.
Funding: This work is supported by a fellowship from JSPS (RPD) and grants from AMED (16mk0104027h1102, 16mk0104007h0003) and MEXT (15H04684).
Provenance: This is a Guest Commentary commissioned by Section Editor Hongcheng Zhu, MD, PhD (Department of Radiation Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China).
Conflicts of Interest: The authors have no conflicts of interest to declare.