Atrazine induces penis abnormalities including hypospadias in mice

Abstract

Use of the herbicide atrazine (ATR) is banned in the European Union; yet, it is still widely used in the USA and Australia. ATR is known to alter testosterone and oestrogen production and thus reproductive characteristics in numerous species. In this proof of concept study, we examined the effect of ATR exposure, at a supra-environmental dose (5 mg/kg bw/day), beginning on E9.5 in utero, prior to sexual differentiation of the reproductive tissues, until 26 weeks of age, on the development of the mouse penis. Notably, this is the first study to specifically investigate whether ATR can affect penis characteristics. We show that ATR exposure, beginning in utero, causes a shortening (demasculinisation) of penis structures and increases the incidence of hypospadias in mice. These data indicate the need for further studies of ATR on human reproductive development and fertility, especially considering its continued and widespread use.

Prenatal exposure to atrazine induces cryptorchidism and hypospadias in F1 male mouse offspring

“…Although the dose (i.e., 100 mg/kg/day) leading to a relatively high occurrence rate of hypospadias and cryptorchidism is much greater than environmental exposure levels in most cases, it does relate to a commonly used reference dose for reproductive effect endpoints in rodents (Rayner et al, 2004). That low dose of ATZ could induce distal tip hypospadias was also consistent with the recently reported findings (Govers et al, 2020). The results suggest that such a low reference dose should be re‐considered for future investigation of ATZ's reproductive developmental effects via animal models.…”

“…Of them, one study reported associations between medium‐low levels of periconceptional maternal ATZ exposure and male genital malformations, including hypospadias and cryptorchidism (Agopian et al, 2013). Literature search revealed only two animal studies related to the effect of ATZ on hypospadias (Govers et al, 2020; Wu et al, 2007), while nothing has been done through animal models to evaluate cryptorchidism induction following ATZ exposure.…”

Endocrine disrupting chemicals in the pathogenesis of hypospadias; developmental and toxicological perspectives

“…However, estrogen receptors are also present in the penis and isolated penis cultures have demonstrated that estrogen and estrogenic EDCs can directly activate these to cause hypospadias, independent of altered hormonal outputs from the gonads ( Fig. 3 ) ( Govers et al, 2020 , Govers et al, 2019b ). Thus, the penis also appears to be a direct target of EDCs in the development of hypospadias.…”

“…It should also be noted that although chemicals are often classified as either estrogen agonists or anti-androgens, estrogen agonists also suppress androgen output from the testis. EDCs Sources Mechanism Impact on urethra development References Atrazine Herbicide ER agonist Association with hypospadias ( Agopian et al, 2013 , Garcia et al, 2017 , Govers et al, 2019a , Kraft et al, 2010 , Kristensen et al, 1997 , Morales-Suarez-Varela et al, 2011 ) BPA Polycarbonate plastics, epoxy resins, plastic toys and bottles, lining of food cans ER agonist Antiandrogen Association with hypospadias ( Choi et al, 2012 , Fernandez et al, 2016 , Liu et al, 2015 ) Clomiphene, progestins, oral contraceptives Pharmaceuticals ER agonist/antagonist Mixed results -Moderate and severe hypospadias increased ( Carmichael et al, 2005 , Meijer et al, 2006 , van Rooij et al, 2013 ) DES Historical pharmaceutical ER agonist Hypospadias ( Kalfa et al, 2011a , Klip et al, 2002 , Mahawong et al, 2014 , Palmer et al, 2005 , Vorherr et al, 1979 ) DDT Contaminated water, soil, fish, crops ER agonist Antiandrogen Association with hypospadias ( Bornman et al, 2010 , Fernandez et al, 2007 ) Genistein Phytoestrogen in legumes and clover ER agonist Hypospadias ( Michikawa et al, 2019 , Moule, 1961 , North and Golding, 2000 , Padilla-Banks et al, 2012 , Ross et al, 2011 , ...…”

“…Atrazine also suppresses Srd5a2 in rats leading to a reduction in the conversion of testosterone into dihydrotestosterone (DHT) ( Holloway et al, 2008 , Jin et al, 2013 , Kniewald et al, 1995 ). Atrazine exposure during pregnancy induces a shortening of penis structures and increases the incidence of hypospadias in mice ( Govers et al, 2019a ). An association between hypospadias and estimated medium levels of maternal atrazine exposure has been identified in humans, particularly for more severe, posterior hypospadias ( Agopian et al, 2013 ).…”