Loratadine Exerts Estrogen-Like Effects and Disrupts Penile Development in the Mouse

Willingham, Emily; Agras, Koray; Vilela, Marcelo; Baskin, Laurence S.

doi:10.1016/s0022-5347(05)00188-6

Cited by 20 publications

(13 citation statements)

References 9 publications

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“…This association may be attributed to the gonadotropin-releasing hormone agonism of valproic acid, which has anti-androgenic effects long-term (Rodriguez-Pinilla and others, 2008). Corticosteroids, which have anti-androgenic properties, and loratadine, which has estrogenic properties, can both induce hypospadias experimentally (Ajayi and Fadiran, 1999; Lipworth, 1999; Negulescu and others, 1977; Reinisch and others, 1978; Willingham and others, 2006; Yucel and others, 2004a). They do not, however, appear to be associated with hypospadias risk in humans (Carmichael and others, 2009; CDC, 2004; Kallen and Olausson, 2006; 2007; Pedersen and others, 2008; Pedersen and others, 2006; Sorensen and others, 2005a).…”

Section: Endocrine Disruptionmentioning

confidence: 99%

Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence

Carmichael

Shaw

Lammer³

2012

Birth Defects Research

109

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This review evaluates current knowledge related to trends in the prevalence of hypospadias, the association of hypospadias with endocrine-disrupting exposures, and the potential contribution of genetic susceptibility to its etiology. The review focuses on epidemiologic evidence. Increasing prevalence of hypospadias has been observed, but such increases tend to be localized to specific regions or time periods. Thus, generalized statements that hypospadias is increasing are unsupported. Due to limitations of study designs and inconsistent results, firm conclusions cannot be made regarding the association of endocrine-disrupting exposures with hypospadias. Studies with more rigorous study designs (e.g., larger and more detailed phenotypes) and exposure assessment that encompasses more breadth as well as depth (e.g., specific endocrine-related chemicals) will be critical to make better inferences about these important environmental exposures. Many candidate genes for hypospadias have been identified, but few of them have been examined to an extent that enables solid conclusions. Further studies are needed that include larger sample sizes, comparison groups that are more representative of the populations from which the cases were derived, phenotype-specific analyses, and more extensive exploration of variants. In conclusion, examining the associations of environmental and genetic factors with hypospadias remain important areas of inquiry, although our actual understanding of their contribution to hypospadias risk in humans is currently limited.

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Section: Endocrine Disruptionmentioning

confidence: 99%

Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence

Carmichael

Shaw

Lammer³

2012

Birth Defects Research

109

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“…6,7 agents that have been implicated in the aetiology of hypospadias based upon epidemiological studies in humans and experimental animal studies include progestins, oestrogens, loratidine and various agents that produce an 'androgen blockade' , including phthalates and anti-androgenic fungicides such as vinclozolin and procymidone. [8][9][10][11][12][13][14][15][16][17][18] a persistent question exists concerning the relevance of animal models to human hypospadias.…”

Section: Introductionmentioning

confidence: 99%

Current understanding of hypospadias: relevance of animal models

et al. 2015

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| Hypospadias is a congenital abnormality of the penile urethra with an incidence of approximately 1:200-1:300 male births, which has doubled over the past three decades. The aetiology of the overwhelming majority of hypospadias remains unknown but appears to be a combination of genetic susceptibility and prenatal exposure to endocrine disruptors. Reliable animal models of hypospadias are required for better understanding of the mechanisms of normal penile urethral formation and hence hypospadias. Mice and/ or rats are generally used for experimental modelling of hypospadias, however these do not fully reflect the human condition. To use these models successfully, researchers must understand the similarities and differences between mouse, rat and human penile anatomy as well as the normal morphogenetic mechanisms of penile development in these species. Despite some important differences, numerous features of animal and human hypospadias are shared: the prevalence of distal penile malformations; disruption of the urethral meatus; disruption of urethra-associated erectile bodies; and a common mechanism of impaired epithelial fusion events. Rat and mouse models of hypospadias are crucial to our understanding of hypospadias to ultimately reduce its incidence through better preventive strategies.

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“…Progestins have been implicated as a potential cause of hypospadias in both animal and human studies (Carmichael et al, 2005; Willingham et al, 2006a; Agras et al, 2007). Animal models of hypospadias have demonstrated a causal relationship between hypospadias and prenatal exposure to a variety of agents: estrogens, progesterone, Loratidine, “androgen blockers” (flutamide, finasteride, anti-androgenic fungicides [vinclozolin and procymidone], and phthalates) (Clark et al, 1993; Ostby et al, 1999; Kojima et al, 2002; Kim et al, 2004; Carmichael et al, 2005; Foster and Harris, 2005; Buckley et al, 2006; Willingham et al, 2006b; Ormond et al, 2009; Rider et al, 2009). The persistent question concerns the relevance of animal models to human hypospadias (Cunha et al, 2015b).…”

Section: Introductionmentioning

confidence: 99%

Diethylstilbestrol-induced mouse hypospadias: “window of susceptibility”

et al. 2016

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Hypospadias, an abnormality affecting the penile urethra, is one of the most prevalent congenital malformations afflicting human males. The morphology of hypospadias is markedly different in humans versus mice reflecting substantial differences in penile development in humans and mice. Estrogens such as diethylstilbestrol (DES) elicit mouse penile malformations, but the types of penile abnormalities differ depending on whether DES treatment is prenatal or neonatal. To define the actual “window of susceptibility” to the adverse effects of DES, pregnant mice and their neonatal pups were injected subcutaneously with 200ng/gbw DES every other day from embryonic day 12 to 18 (DES E12-E18), postnatal day 0 to 10 (DES P0-P10), embryonic day 12 to postnatal day 10 (DES E12 to P10), postnatal day 5 to 15 (DES P5 to P15), and postnatal day 10 to 20 (DES P10 to P20). Aged-matched controls received sesame oil vehicle. After euthanasia at 10, 15, 20 and 60 days, penises were analyzed by gross morphology, histology and morphometry. Penises of all 5 groups of DES-treated mice were reduced in size, which was confirmed by morphometric analysis of internal penile structures. The most profound effects were seen in the DES E12-P10, DES P0-P10, and DES P5-P15 groups, thus defining a DES “programming window”. For all parameters, DES treatment from P10-P20 showed the most mild of effects. Adverse effects of DES on the MUMP cartilage and erectile bodies observed shortly after the last DES injection reverted to normality in the DES P5-P15, but not in the E12-P10 and P0-P10 groups, in which MUMP cartilage and erectile body malformations persisted into adulthood, again emphasizing a “window of susceptibility” in the early neonatal period.

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Loratadine Exerts Estrogen-Like Effects and Disrupts Penile Development in the Mouse

Abstract: In utero exposure to over-the-counter loratadine syrup can result in hypospadias in this model, and creates changes in the steroid receptor mRNA expression profile similar to those elicited by a synthetic estrogen.

Cited by 20 publications

References 9 publications

Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence

Environmental and genetic contributors to hypospadias: A review of the epidemiologic evidence

Current understanding of hypospadias: relevance of animal models

Diethylstilbestrol-induced mouse hypospadias: “window of susceptibility”

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