Hostname: page-component-586b7cd67f-t7fkt Total loading time: 0 Render date: 2024-11-23T11:00:27.007Z Has data issue: false hasContentIssue false

Atrazine induces penis abnormalities including hypospadias in mice

Published online by Cambridge University Press:  02 September 2019

Luke C. Govers
Affiliation:
School of BioSciences, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
Alesia P. Harper
Affiliation:
School of BioSciences, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
Bethany J. Finger
Affiliation:
School of BioSciences, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
Deidre M. Mattiske
Affiliation:
School of BioSciences, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
Andrew J. Pask
Affiliation:
School of BioSciences, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
Mark P. Green*
Affiliation:
School of BioSciences, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia
*
Address for correspondence: Dr. Mark Green, School of BioSciences, University of Melbourne, Parkville, Melbourne, VIC 3010, Australia. Email: [email protected]

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.

Type
Brief Report
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

Joint senior authors

References

Paulozzi, LJ.International trends in rates of hypospadias and cryptorchidism. Environ Health Perspect. 1999; 107, 297302. DOI: 10.1289/ehp.99107297.CrossRefGoogle ScholarPubMed
Nassar, N, Bower, C, Barker, A.Increasing prevalence of hypospadias in Western Australia, 1980-2000. Arch Dis Child. 2007; 92, 580584. DOI: 10.1136/adc.2006.112862.CrossRefGoogle ScholarPubMed
Bouty, A, Ayers, KL, Pask, AJ, Helourry, Y, Sinclair, AH.The genetic and environmental factors underlying hypospadias. Sex Dev. 2015; 9, 239259. DOI: 10.1159/000441988.CrossRefGoogle ScholarPubMed
Govers, LC, Phillips, TR, Mattiske, DM, et al.A critical role for estrogen signaling in penis development. FASEB J. 2019; accepted 3rd June 2019. DOI: 10.1096/fj.201802586RR.CrossRefGoogle Scholar
Gore, AC, Chappell, VA, Fenton, SE, et al.EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr Rev. 2015; 36, E1E150. DOI: 10.1210/er.2015-1010.CrossRefGoogle ScholarPubMed
Skakkebaek, NE, Raipert-De Meyts, E, Buck, GM, et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev. 2016; 96, 5597. DOI: 10.1152/physrev.00017.2015.CrossRefGoogle ScholarPubMed
Bonde, JP, Flachs, EM, Rimborg, S, et al. The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systemic review and meta-analysis. Hum Reprod Update. 2017; 23, 104125. DOI: 10.1093/humupd/dmw036.CrossRefGoogle Scholar
United Nations Environmental Programme & World Health Organization. In State of the Science of Endocrine Disrupting Chemicals-2012 (eds. Bergman, A, Heindel, JJ, Jobling, S, Kidd, SA, Zoeller, RT), 2013; pp. 1289. United Nations Environmental Programme & World Health Organization, Geneva, Switzerland.Google Scholar
Farruggia, FT, Rossmeisl, CM, Hetrick, JA, Biscoe, M, Branch, MER, III. Refined Ecological Risk Assessment for Atrazine, 2016. US Environmental Protection Agency, Office of Pesticide Programs, Washington DC, USA.Google Scholar
Mnif, W, Hassine, AI, Bouaziz, A, Bartegi, A, Thomas, O, Roig, B.Effect of endocrine disruptor pesticides: a review. Int J Environ Res Public Health. 2011; 8, 22652303. DOI: 10.3390/ijerph8062265.CrossRefGoogle ScholarPubMed
Jin, YX, Wang, LG, Fu, ZW.Oral exposure to atrazine modulates hormone synthesis and the transcription of steroidogenic genes in male peripubertal mice. Gen Comp Endocrinol. 2013; 184, 120127. DOI: 10.1016/j.ygcen.2013.01.010.CrossRefGoogle ScholarPubMed
Holloway, AC, Anger, DA, Crankshaw, DJ, Wu, M, Foster, WG.Atrazine-induced changes in aromatase activity in estrogen sensitive target tissues. J Appl Toxicol. 2008; 28, 260270. DOI: 10.1002/jat.1275.CrossRefGoogle ScholarPubMed
Kniewald, J, Osredecki, V, Gojmerac, T, Zechner, V, Kniewald, Z.Effect of s-triazine compounds on testosterone metabolism in the rat prostate. J Appl Toxicol. 1995; 15, 215218. DOI: 10.1002/jat.2550150312.CrossRefGoogle ScholarPubMed
Blaschko, SD, Mahawong, P, Ferretti, M, et al.Analysis of the effect of estrogen/androgen perturbation on penile development in transgenic and diethystilbesterol-treated mice. Anat Rec. 2013; 296, 11271141. DOI: 10.1002/ar.22708.CrossRefGoogle ScholarPubMed
Phillips, TR, Wright, DK, Gradie, PE, Johnston, LA, Pask, AJ.A comprehensive atlas of the adult mouse penis. Sex Dev. 2015; 9, 162172. DOI: 10.1159/000431010.CrossRefGoogle ScholarPubMed
Fischer, AH, Jacobson, KA, Rose, J, Zeller, R.Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc. 2008; 5, pdb.prot4986. DOI: 10.1101/pdb.prot4986.CrossRefGoogle Scholar
Mahawong, P, Sinclair, A, Li, Y, et al.Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains. Differentiation. 2014; 88, 5169. DOI: 10.1016/j.diff.2014.09.005.CrossRefGoogle ScholarPubMed
EU Commission. Commission decision of 10 March 2004 concerning the non-inclusion of atrazine in Annex I to Council Directive 91/414/EEC and the withdrawal of authorisations for plant protection products containing this active substance. J Eur Union. 2004; 78, 5355.Google Scholar
Australian Pesticides and Veterinary Medicines Authority. Technical report: environmental assessment, 2004; Canberra, Australia. Available from: https://apvma.gov.au/node/14356 [cited 2018 Dec 23].Google Scholar
US Environmental Protection Agency (EPA) Interim Reregistration Eligibility Decision for Atrazine 2005, 2003; US EPA, Washington DC, USA.Google Scholar
Victor-Costa, AB, Bandeira, SM, Oliveira, AG, Mahecha, GA, Oliveira, CA.Changes in testicular morphology and steroidogenesis in adult rats exposed to Atrazine. Reprod Toxicol. 2010; 29, 323331. DOI: 10.1016/j.reprotox.2009.12.006.CrossRefGoogle ScholarPubMed
Gely-Pernot, A, Hao, C, Becker, E, et al.The epigenetic processes of meiosis in male mice are broadly affected by the widely used herbicide atrazine. BMC Genomics. 2015; 16, 885. DOI: 10.1186/s12864-015-2095-y.CrossRefGoogle ScholarPubMed
Chen, Y, Yu, HS, Pask, AJ, et al. Hormone-responsive genes in the SHH and WNT/beta-catenin signaling pathways influence urethral closure and phallus growth. Biol Reprod. 2018; 99, 806816. DOI: 10.1093/biolre/ioy117.Google ScholarPubMed
Sinclair, AW, Cao, M, Baskin, L, Cunha, GR.Diethylstilbesterol-induced mouse hypospadias: “window of susceptibility”. Differentiation. 2016; 91, 118. DOI: 10.1016/j.diff.2016.01.004.CrossRefGoogle Scholar
Swan, SH, Kruse, RL, Liu, F, et al.Semen quality in relation to biomarkers of pesticide exposure. Environ Health Perspect. 2003; 111, 14781484. DOI: 10.1289/ehp.6417.CrossRefGoogle ScholarPubMed