Reproductive toxicity following in utero and lactational exposure to a human-relevant phthalate mixture in rats.

Autor:	Curi TZ; Reproductive Toxicology Laboratory, Department of Pharmacology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil., Passoni MT; Reproductive Toxicology Laboratory, Department of Pharmacology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil., Lima Tolouei SE; Reproductive Toxicology Laboratory, Department of Pharmacology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil., de Araújo Ramos AT; Animal Endocrine and Reproductive Physiology Laboratory, Department of Physiology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil., França de Almeira SC; Animal Endocrine and Reproductive Physiology Laboratory, Department of Physiology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil., Scinskas ABAF; Animal Endocrine and Reproductive Physiology Laboratory, Department of Physiology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil., Romano RM; Reproductive Toxicology Laboratory, Department of Pharmacy, State University of Centro-Oeste, Guarapuava, PR 85040-167, Brazil., de Oliveira JM; Reproductive Toxicology Laboratory, Department of Pharmacy, State University of Centro-Oeste, Guarapuava, PR 85040-167, Brazil., Spercoski KM; Department of Biosciences, Federal University of Paraná (UFPR), Palotina, PR 85950-000, Brazil., Carvalho Dos Santos A; Histopathology Laboratory, Department of Health Sciences, Federal University of Grande Dourados (UFGD), Dourados, MS 9804-970, Brazil., Dalsenter PR; Reproductive Toxicology Laboratory, Department of Pharmacology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil., Koch HM; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University-Bochum (IPA), Bochum 44789, Germany., Martino-Andrade AJ; Reproductive Toxicology Laboratory, Department of Pharmacology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil.; Animal Endocrine and Reproductive Physiology Laboratory, Department of Physiology, Federal University of Paraná (UFPR), Curitiba, PR 81531-990, Brazil.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2023 Dec 21; Vol. 197 (1), pp. 1-15.
DOI:	10.1093/toxsci/kfad102
Abstrakt:	This rodent (Wistar rats) study examined reproductive effects of in utero/lactational exposure to a mixture of 6 antiandrogenic phthalates (PMix): diisobutyl phthalate, di-n-butyl phthalate, diisopentyl phthalate, butylbenzyl phthalate, di-2-ethylhexyl phthalate, and diisononyl phthalate. The PMix was defined based on exposure data from pregnant women in Brazil. Experimental groups were established by extrapolating the estimated human dose to rats (0.1 mg/kg/day), followed by up to 3 additional doses corresponding to 5, 1000, and 5000 times the starting rat dose: 0 (control), 0.1, 0.5, 100, and 500 mg/kg/day. The fetal experiment assessed gestational exposure effects on fetal gonads, whereas the postnatal experiment evaluated reproductive parameters in males and females after in utero and lactational exposure. Prenatal exposure decreased fetal testicular testosterone production at 0.5 and 500 mg/kg/day. PMix 500 also reduced mRNA expression of steroidogenesis-related genes, upregulated transcript expression of the retinoic acid-degrading enzyme Cyp26b1, and increased multinucleated gonocytes incidence in fetal testes. Postnatal assessment revealed antiandrogenic effects at the highest dose, including reduced anogenital distance, nipple retention, and decreased weight of reproductive organs. Early puberty onset (preputial separation) was observed at the lowest dose in males. In contrast, females did not show significant changes in fetal and adult endpoints. Overall, the PMix recapitulated early and late male rat phthalate syndrome phenotypes at the highest dose, but also induced some subtle changes at lower doses, which warrant confirmation and mechanistic assessments. Our data support the use of epidemiologically defined mixtures for exposure risk assessments over traditional toxicological approaches. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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