Abstract
Developmental toxicology is a constantly evolving research field which needs to attend to a complex underlying regulatory network. In order to ensure human health and environmental safety, new substances have to be tested for toxic effects on reproduction and development, before being commercialized. Traditional in vivo mammalian models represent the intricacy of human development and provide more adequately an assessment of the interaction of chemical compounds with the reproductive system. However, in the last years, the directives are to reduce the use of vertebrate animals, promoting their use only as a last resort. Consequently, the interest on the development and validation of alternative tests, able to cover the various aspects of the reproductive cycle, has significantly increased. Reproductive toxicity is probably the most difficult endpoint to be replaced by alternative assays, since it should provide information on mechanism interactions essential for female and male fertility and also knowledge on the animal development during the first phases of its life cycle. This complexity explains the slow progress in implementing alternative models for reproductive toxicity safety assays. Alternative test models may be based on in vitro systems and nonmammalian animal models. Many biological processes have been successfully addressed using in vitro models, opening the possibility to study the interference of teratogenic compounds. Their validation and implementation have lagged behind, in part because of difficulties in establishing their predictability. Nevertheless, the advance toward the process of validation is crucial to replace and reduce the use of living animals. Based on the present state of the art, it is not probable that such testing strategies will completely replace the need to assess reproductive toxicity in vivo in the near future, but they will contribute to reduce animal tests and will provide important information. In this chapter, the approved guidelines for standard methods and alternative methods, according to their regulatory and scientific status, are enumerated and briefly described.
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Tyl RW (2010) In honor of the Teratology Society’s 50th anniversary: the role of Teratology Society members in the development and evolution of in vivo developmental toxicity test guidelines. Birth Defects Res C Embryo Today 90(2):99–102. https://doi.org/10.1002/bdrc.20176
http://jacvam.jp/en. Accessed 15 Dec 2017
Kaltenhauser J, Kneuer C, Marx-Stoelting P, Niemann L, Schubert J, Stein B, Solecki R (2017) Relevance and reliability of experimental data in human health risk assessment of pesticides. Regul Toxicol Pharmacol 88:227–237. https://doi.org/10.1016/j.yrtph.2017.06.010
Bolon B, Barale-Thomas E, Bradley A, Ettlin RA, Franchi CA, George C, Giusti AM, Hall R, Jacobsen M, Konishi Y, Ledieu D, Morton D, Park JH, Scudamore CL, Tsuda H, Vijayasarathi SK, Wijnands MV (2010) International recommendations for training future toxicologic pathologists participating in regulatory-type, nonclinical toxicity studies. J Toxicol Pathol 23(3):171–181. https://doi.org/10.1293/tox.23.171
Hood RD (2006) Principles of developmental toxicology revisited. In: Hood RD (ed) Developmental and reproductive toxicology: a practical approach. CRC Press, Boca Raton, pp 3–14
Fenner-Crisp PA, Dellarco VL (2016) Key elements for judging the quality of a risk assessment. Environ Health Perspect 124(8):1127–1135. https://doi.org/10.1289/ehp.1510483
Pamis DE, Estevan C, Vilanova E, Sogorb MA (2017) Validated and nonvalidated mechanism-based methods for testing development toxicity. In: Gupta RC (ed) Reproductive and developmental toxicology. Academic Press, London, pp 193–209
Adler S, Basketter D, Creton S, Pelkonen O, van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A, Benfenati E, Bernauer U, Bessems J, Bois FY, Boobis A, Brandon E, Bremer S, Broschard T, Casati S, Coecke S, Corvi R, Cronin M, Daston G, Dekant W, Felter S, Grignard E, Gundert-Remy U, Heinonen T, Kimber I, Kleinjans J, Komulainen H, Kreiling R, Kreysa J, Leite SB, Loizou G, Maxwell G, Mazzatorta P, Munn S, Pfuhler S, Phrakonkham P, Piersma A, Poth A, Prieto P, Repetto G, Rogiers V, Schoeters G, Schwarz M, Serafimova R, Tahti H, Testai E, van Delft J, van Loveren H, Vinken M, Worth A, Zaldivar JM (2011) Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol 85(5):367–485. https://doi.org/10.1007/s00204-011-0693-2
http://ecvam.jrc.it. Accessed 15 Dec 2014
Edgar BA, Kiehle CP, Schubiger G (1986) Cell cycle control by the nucleo-cytoplasmic ratio in early Drosophila development. Cell 44(2):365–372
Sulston JE, Horvitz HR (1977) Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1):110–156
Sulston JE, Schierenberg E, White JG, Thomson JN (1983) The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100(1):64–119
Hartung T (2009) Toxicology for the twenty-first century. Nature 460(7252):208–212. https://doi.org/10.1038/460208a
Andrew W, Filipe VBJ, Susanne B, Julien B, Silvia C, Sandra C, Raffaella C, Bertrand D, Coralie D, Varvara G, Paraskevi GM, Rabea G, Claudius G, Elisabeth HM, Annett JR, Aude K, Federica M, Sharon M, Malgorzata N, Alicia P, Anna P, PPMD P, Alexandra R, Wilhelm SM, Jutta T, Maurice W, Clemens W, Valerie Z (2014) Alternative methods for regulatory toxicology – a state-of-the-art review. https://doi.org/10.2788/11111
europa.eu/!uC38HQ. 15 Dec 2017
(2020) ICH Final Version ICH Harmonised Guideline S5(R3): detection of reproductive and developmental toxicity for human pharmaceuticals. In: International conference on harmonization [ICH]. ICH, Geneva
Chapman KL, Holzgrefe H, Black LE, Brown M, Chellman G, Copeman C, Couch J, Creton S, Gehen S, Hoberman A, Kinter LB, Madden S, Mattis C, Stemple HA, Wilson S (2013) Pharmaceutical toxicology: designing studies to reduce animal use, while maximizing human translation. Regul Toxicol Pharmacol 66(1):88–103. https://doi.org/10.1016/j.yrtph.2013.03.001
Hamm J, Sullivan K, Clippinger AJ, Strickland J, Bell S, Bhhatarai B, Blaauboer B, Casey W, Dorman D, Forsby A, Garcia-Reyero N, Gehen S, Graepel R, Hotchkiss J, Lowit A, Matheson J, Reaves E, Scarano L, Sprankle C, Tunkel J, Wilson D, Xia M, Zhu H, Allen D (2017) Alternative approaches for identifying acute systemic toxicity: moving from research to regulatory testing. Toxicol In Vitro 41:245–259. https://doi.org/10.1016/j.tiv.2017.01.004
Barrow P (2016) Revision of the ICH guideline on detection of toxicity to reproduction for medicinal products: SWOT analysis. Reprod Toxicol 64:57–63. https://doi.org/10.1016/j.reprotox.2016.03.048
Kleinstreuer NC, Yang J, Berg EL, Knudsen TB, Richard AM, Martin MT, Reif DM, Judson RS, Polokoff M, Dix DJ, Kavlock RJ, Houck KA (2014) Phenotypic screening of the ToxCast chemical library to classify toxic and therapeutic mechanisms. Nat Biotechnol 32(6):583–591. https://doi.org/10.1038/nbt.2914
Piersma AH (2006) Alternative methods for developmental toxicity testing. Basic Clin Pharmacol Toxicol 98(5):427–431. https://doi.org/10.1111/j.1742-7843.2006.pto_373.x
van Dartel DA, Pennings JL, de la Fonteyne LJ, van Herwijnen MH, van Delft JH, van Schooten FJ, Piersma AH (2010) Monitoring developmental toxicity in the embryonic stem cell test using differential gene expression of differentiation-related genes. Toxicol Sci 116(1):130–139. https://doi.org/10.1093/toxsci/kfq127
Schumann J (2010) Teratogen screening: state of the art. Avicenna J Med Biotechnol 2(3):115–121
Flint OP (1993) In vitro tests for teratogens: desirable endpoints, test batteries and current status of the micromass teratogen test. Reprod Toxicol 7(Supplement 1):103–111. https://doi.org/10.1016/0890-6238(93)90075-I
Marx-Stoelting P, Adriaens E, Ahr H-J, Bremer S, Garthoff B, Gelbke H-P, Piersma A, Pellizzer C, Reuter U, Rogiers V, Schenk B, Schwengberg S, Seiler A, Spielmann H, Steemans M, Stedman D, Vanparys P, Albert Vericat J, Verwei M, Schwarz M (2009) A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect Workshop. Altern Lab Anim 37:313–328
Spielmann H, Seiler A, Bremer S, Hareng L, Hartung T, Ahr H, Faustman E, Haas U, Moffat GJ, Nau H, Vanparys P, Piersma A, Sintes JR, Stuart J (2006) The practical application of three validated in vitro embryotoxicity tests. The report and recommendations of an ECVAM/ZEBET workshop (ECVAM workshop 57). Altern Lab Anim 34(5):527–538
ISO (2012) Soil quality — effects of pollutants on earthworms — part 1: determination of acute toxicity to Eisenia fetida/Eisenia Andrei. 11268-1
ISO (2008) Soil quality – avoidance test for determining the quality of soils and effects of chemicals on behaviour – part 1: test with earthworms (Eisenia fetida and Eisenia andrei) 17512–1
Wise LD (2013) The ICH S5(R2) guideline for the testing of medicinal agents. Methods Mol Biol 947:1–11. https://doi.org/10.1007/978-1-62703-131-8_1
OECD Test No. 231: amphibian metamorphosis assay. OECD Publishing, Paris
Mouche I, Malesic L, Gillardeaux O (2011) FETAX assay for evaluation of developmental toxicity. Methods Mol Biol 691:257–269. https://doi.org/10.1007/978-1-60761-849-2_15
Weigt S, Huebler N, Strecker R, Braunbeck T, Broschard TH (2011) Zebrafish (Danio rerio) embryos as a model for testing proteratogens. Toxicology 281(1–3):25–36. https://doi.org/10.1016/j.tox.2011.01.004
de Esch C, Slieker R, Wolterbeek A, Woutersen R, de Groot D (2012) Zebrafish as potential model for developmental neurotoxicity testing: a mini review. Neurotoxicol Teratol 34(6):545–553. https://doi.org/10.1016/j.ntt.2012.08.006
Strahle U, Scholz S, Geisler R, Greiner P, Hollert H, Rastegar S, Schumacher A, Selderslaghs I, Weiss C, Witters H, Braunbeck T (2012) Zebrafish embryos as an alternative to animal experiments--a commentary on the definition of the onset of protected life stages in animal welfare regulations. Reprod Toxicol 33(2):128–132. https://doi.org/10.1016/j.reprotox.2011.06.121
Braunbeck T, Kais B, Lammer E, Otte J, Schneider K, Stengel D, Strecker R (2015) The fish embryo test (FET): origin, applications, and future. Environ Sci Pollut Res Int 22(21):16247–16261. https://doi.org/10.1007/s11356-014-3814-7
Carney EW, Scialli AR, Watson RE, DeSesso JM (2004) Mechanisms regulating toxicant disposition to the embryo during early pregnancy: an interspecies comparison. Birth Defects Res C Embryo Today 72(4):345–360. https://doi.org/10.1002/bdrc.20027
Kochhar DM (1980) In vitro testing of teratogenic agents using mammalian embryos. Teratog Carcinog Mutagen 1(1):63–74
Fantel AG (1982) Culture of whole rodent embryos in teratogen screening. Teratog Carcinog Mutagen 2(3–4):231–242
Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, Lilly P, Sanders J, Sipes G, Bracken W, Dorato M, Van Deun K, Smith P, Berger B, Heller A (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32(1):56–67. https://doi.org/10.1006/rtph.2000.1399
Christian MSHAM, Lewis EM (2006) Perspectives on the developmental and reproductive toxicity guidelines. In: Hood RD (ed) Developmental and reproductive toxicology: a practical approach. CRC Press, Boca Raton, pp 733–798
OECD Test No. 414: prenatal development toxicity study. OECD Publishing, Paris
OECD Test No. 443: extended one-generation reproductive toxicity study. OECD Publishing, Paris
Dietert RR (2009) Developmental immunotoxicology: focus on health risks. Chem Res Toxicol 22(1):17–23. https://doi.org/10.1021/tx800198m
Kraft AD, Aschner M, Cory-Slechta DA, Bilbo SD, Caudle WM, Makris SL (2016) Unmasking silent neurotoxicity following developmental exposure to environmental toxicants. Neurotoxicol Teratol 55:38–44. https://doi.org/10.1016/j.ntt.2016.03.005
Solecki R, Kortenkamp A, Bergman A, Chahoud I, Degen GH, Dietrich D, Greim H, Hakansson H, Hass U, Husoy T, Jacobs M, Jobling S, Mantovani A, Marx-Stoelting P, Piersma A, Ritz V, Slama R, Stahlmann R, van den Berg M, Zoeller RT, Boobis AR (2017) Scientific principles for the identification of endocrine-disrupting chemicals: a consensus statement. Arch Toxicol 91(2):1001–1006. https://doi.org/10.1007/s00204-016-1866-9
Saghir SA, Dorato MA (2016) Reproductive and developmental toxicity testing: examination of the extended one-generation reproductive toxicity study guideline. Regul Toxicol Pharmacol 79:110–117. https://doi.org/10.1016/j.yrtph.2016.03.023
Hunt PR (2017) The C. elegans model in toxicity testing. J Appl Toxicol 37(1):50–59. https://doi.org/10.1002/jat.3357
Lemeire K, Van Merris V, Cortvrindt R (2007) The antibiotic streptomycin assessed in a battery of in vitro tests for reproductive toxicology. Toxicol In Vitro 21(7):1348–1353. https://doi.org/10.1016/j.tiv.2007.05.004
Genschow E, Spielmann H, Scholz G, Pohl I, Seiler A, Clemann N, Bremer S, Becker K (2004) Validation of the embryonic stem cell test in the international ECVAM validation study on three in vitro embryotoxicity tests. Altern Lab Anim 32(3):209–244
Hareng L, Pellizzer C, Bremer S, Schwarz M, Hartung T (2005) The Integrated Project ReProTect: a novel approach in reproductive toxicity hazard assessment. Reprod Toxicol 20(3):441–452. https://doi.org/10.1016/j.reprotox.2005.04.003
Spielmann H, Genschow E, Brown NA, Piersma AH, Verhoef A, Spanjersberg MQ, Huuskonen H, Paillard F, Seiler A (2004) Validation of the rat limb bud micromass test in the international ECVAM validation study on three in vitro embryotoxicity tests. Altern Lab Anim 32(3):245–274
Selderslaghs IW, Van Rompay AR, De Coen W, Witters HE (2009) Development of a screening assay to identify teratogenic and embryotoxic chemicals using the zebrafish embryo. Reprod Toxicol 28(3):308–320. https://doi.org/10.1016/j.reprotox.2009.05.004
Brannen KC, Panzica-Kelly JM, Danberry TL, Augustine-Rauch KA (2010) Development of a zebrafish embryo teratogenicity assay and quantitative prediction model. Birth Defects Res B Dev Reprod Toxicol 89(1):66–77. https://doi.org/10.1002/bdrb.20223
Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (2010) Identification of a primary target of thalidomide teratogenicity. Science 327(5971):1345–1350. https://doi.org/10.1126/science.1177319
Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 4(1):35–44. https://doi.org/10.1038/nrd1606
Fort DJ, Paul RR (2002) Enhancing the predictive validity of Frog Embryo Teratogenesis Assay--Xenopus (FETAX). J Appl Toxicol 22(3):185–191. https://doi.org/10.1002/jat.848
La Sala G, Farini D, De Felici M (2010) Estrogenic in vitro assay on mouse embryonic Leydig cells. Int J Dev Biol 54(4):717–722. https://doi.org/10.1387/ijdb.092883gs
Schleh C, Leoni A-L (2013) How to optimize the benefits of computer assisted sperm analysis in experimental toxicology. J Occup Med Toxicol (London, England) 8:6–6. https://doi.org/10.1186/1745-6673-8-6
Myren M, Mose T, Mathiesen L, Knudsen LE (2007) The human placenta--an alternative for studying foetal exposure. Toxicol In Vitro 21(7):1332–1340. https://doi.org/10.1016/j.tiv.2007.05.011
Mose T, Kjaerstad MB, Mathiesen L, Nielsen JB, Edelfors S, Knudsen LE (2008) Placental passage of benzoic acid, caffeine, and glyphosate in an ex vivo human perfusion system. J Toxicol Environ Health A 71(15):984–991. https://doi.org/10.1080/01932690801934513
Myllynen P, Immonen E, Kummu M, Vahakangas K (2009) Developmental expression of drug metabolizing enzymes and transporter proteins in human placenta and fetal tissues. Expert Opin Drug Metab Toxicol 5(12):1483–1499. https://doi.org/10.1517/17425250903304049
Morck TJ, Sorda G, Bechi N, Rasmussen BS, Nielsen JB, Ietta F, Rytting E, Mathiesen L, Paulesu L, Knudsen LE (2010) Placental transport and in vitro effects of Bisphenol A. Reprod Toxicol 30(1):131–137. https://doi.org/10.1016/j.reprotox.2010.02.007
Cordelli E, Fresegna AM, D’Alessio A, Eleuteri P, Spano M, Pacchierotti F, Villani P (2007) ReProComet: a new in vitro method to assess DNA damage in mammalian sperm. Toxicol Sci 99(2):545–552. https://doi.org/10.1093/toxsci/kfm191
Lazzari G, Tessaro I, Crotti G, Galli C, Hoffmann S, Bremer S, Pellizzer C (2008) Development of an in vitro test battery for assessing chemical effects on bovine germ cells under the ReProTect umbrella. Toxicol Appl Pharmacol 233(3):360–370. https://doi.org/10.1016/j.taap.2008.08.019
Luciano AM, Franciosi F, Lodde V, Corbani D, Lazzari G, Crotti G, Galli C, Pellizzer C, Bremer S, Weimer M, Modina SC (2010) Transferability and inter-laboratory variability assessment of the in vitro bovine oocyte maturation (IVM) test within ReProTect. Reprod Toxicol 30(1):81–88. https://doi.org/10.1016/j.reprotox.2010.01.015
Tessaro I, Modina SC, Crotti G, Franciosi F, Colleoni S, Lodde V, Galli C, Lazzari G, Luciano AM (2015) Transferability and inter-laboratory variability assessment of the in vitro bovine oocyte fertilization test. Reprod Toxicol 51:106–113. https://doi.org/10.1016/j.reprotox.2015.01.001
Yang L, Ho NY, Alshut R, Legradi J, Weiss C, Reischl M, Mikut R, Liebel U, Muller F, Strahle U (2009) Zebrafish embryos as models for embryotoxic and teratological effects of chemicals. Reprod Toxicol 28(2):245–253. https://doi.org/10.1016/j.reprotox.2009.04.013
van Thriel C, Westerink RH, Beste C, Bale AS, Lein PJ, Leist M (2012) Translating neurobehavioural endpoints of developmental neurotoxicity tests into in vitro assays and readouts. Neurotoxicology 33(4):911–924. https://doi.org/10.1016/j.neuro.2011.10.002
Iguchi T, Irie F, Urushitani H, Tooi O, Kawashima Y, Roberts M, Norrgren L, Hutchinson T (2006) Availability of in vitro vitellogenin assay for screening of estrogenic and anti-estrogenic activities of environmental chemicals. Environ Sci 13(3):161–183
Acknowledgments
This work was financially supported by Portuguese funds by FCT/MCTES—Portuguese Foundation for Science and Technology/Ministério da Ciência, Tecnologia e Ensino Superior, under the projects UIDB/04033/2020, UIDB/00772/2020, LA/P/0059/2020, and under the Scientific Employment Stimulus—Institutional Call—CEECINST/00127/2018 UTAD (Sofia Alves-Pimenta).
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Alves-Pimenta, S., Félix, L., Colaço, B., Oliveira, P.A., Venâncio, C. (2024). Guidelines on Developmental Toxicity Tests: Brief Insights. In: Félix, L. (eds) Teratogenicity Testing. Methods in Molecular Biology, vol 2753. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3625-1_2
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