In Utero and Lactational Exposure to Diisopentyl Phthalate Induces Fetal Toxicity and Antiandrogenic Effects in Rats Tatiana Zauer Curi,* ,2 Gabriela Neubert da Silva,* ,2 Marcella Tapias Passoni,* Sara Emilia Lima Tolouei,* Helo  ısa Meldola,* Renata Marino Romano, ‡ Nicole Grechi,* Paulo Roberto Dalsenter,* and Anderson Joel Martino-Andrade * ,†,1 *Reproductive Toxicology Laboratory, Department of Pharmacology, Federal University of Paran a (UFPR), Curitiba, PR 81531-980, Brazil; † Animal Endocrine and Reproductive Physiology Laboratory, Department of Physiology, Federal University of Paran a (UFPR), Curitiba, PR 81531-980, Brazil; and ‡ Laboratory of Reproductive Toxicology, Department of Pharmacy, State University of Centro-Oeste, Guarapuava, PR 85040-080, Brazil 1 To whom correspondence should be addressed at Laborat orio de Fisiologia End ocrina e Reprodutiva, Departamento de Fisiologia, Setor de Ci^ encias Biol ogicas, Universidade Federal do Paran a, Centro Polit ecnico—Jardim das Am ericas, PO Box 19031, Curitiba, PR 81531-980, Brazil. Fax: þ55 (41) 33611714. E-mail: anderson.andrade@ufpr.br. 2 These authors contributed equally to this work. ABSTRACT A previous study has demonstrated exposure of Brazilian pregnant women to diisopentyl phthalate (DiPeP), which reduces fetal rat testosterone production in a dose-responsive manner. In this study, we examined gene expression of steroidogenic proteins in rat fetal testes and investigated the effects of in utero and lactational DiPeP exposure on male rat reproductive development and function. For the prenatal experiment, we orally exposed pregnant Wistar rats to DiPeP or di-n-butyl phthalate (reference phthalate) at 0, 125, 250, and 500 mg/kg/day from gestation day 14–18 and the fetal testis was evaluated for transcript expression of Star, Cyp11a1, Cyp17a1, Cyp19a1, Insl3, Ar, Esr1, Esr2, and Gper1 by real-time quantitative PCR (RT-qPCR). Diisopentyl phthalate lowered mRNA levels of key steroidogenic proteins, lending support to the previously reported reductions in fetal testosterone production. Diisopentyl phthalate also lowered fetal testis transcript levels of Insl3 and changed gene expression of some steroid hormones receptors. For the postnatal experiment, pregnant rats were exposed orally to vehicle (canola oil) and 4 DiPeP doses (1, 10, 100, and 300 mg/kg/day) between gestation day 10 and postnatal day 21. Diisopentyl phthalate induced a range of reproductive and antiandrogenic effects that are typical of the rat phthalate syndrome, including reduced anogenital distance at the highest dose, reduced weight of seminal vesicles at 10 mg/kg/day and above, and testicular morphological and functional changes. Signs of fetal toxicity were observed at the highest dose. Together, our results indicate that DiPeP, a compound relevant to the human exposure scenario, is one of the most active antiandrogenic phthalates. Key words: diisoamyl phthalate (DiAP); phthalates; endocrine disruptors; steroidogenesis; reproductive toxicology; Wistar rats. Phthalate esters are a large class of industrial chemicals, ubiqui- tously found in the environment, which have numerous appli- cations in consumer products, including polyvinyl chloride (PVC) plastics, personal care products, medicines, cosmetics, food packaging, medical equipment, toys, paints, and others (Dalsenter et al., 2006; Hannas et al., 2011; Swan et al., 2005). V C The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com 347 TOXICOLOGICAL SCIENCES, 171(2), 2019, 347–358 doi: 10.1093/toxsci/kfz159 Advance Access Publication Date: July 31, 2019 Research Article Downloaded from https://academic.oup.com/toxsci/article/171/2/347/5541806 by guest on 13 July 2022