title: Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters.
abstract: This study examined late-life effects of perinatal exposure of rats to a mixture of endocrine-disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, u.v.-filters, bisphenol A, parabens, and the drug paracetamol. The groups received vehicle (control), a mixture of all 13 chemicals at 150-times (TotalMix150) or 450-times (TotalMix450) high-end human exposure, or 450-times a mixture of nine predominantly anti-androgenic chemicals (AAMix450). Onset of puberty and estrous cyclicity at 9 and 12 months of age were assessed. Few female offspring showed significantly regular estrus cyclicity at 12 months of age in the TotalMix450 and AAMix450 groups compared with controls. In 19-month-old male offspring, epididymal sperm counts were lower than controls, and in ventral prostate an overrepresentation of findings related to hyperplasia was observed in exposed groups compared with controls, particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the AAMix450 group. Developmental exposure of rats to the highest dose of a human-relevant mixture of endocrine disrupters induced adverse effects late in life, manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia, and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.
authors.affiliation: Division of Toxicology and Risk Assessment, National Food Institute, Technical University of Denmark, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark.
authors.forename: Louise Krag
authors.initials: LK
authors.lastname: Isling
authors.forename: Julie
authors.initials: J
authors.lastname: Boberg
authors.forename: Pernille Rosenskjold
authors.initials: PR
authors.lastname: Jacobsen
authors.forename: Karen Riiber
authors.initials: KR
authors.lastname: Mandrup
authors.forename: Marta
authors.initials: M
authors.lastname: Axelstad
authors.forename: Sofie
authors.initials: S
authors.lastname: Christiansen
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Vinggaard
authors.forename: Camilla
authors.initials: C
authors.lastname: Taxvig
authors.forename: Andreas
authors.initials: A
authors.lastname: Kortenkamp
authors.forename: Ulla
authors.initials: U
authors.lastname: Hass
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000375:Aging / Q000187:drug effects*; D000818:Animals; D001559:Benzhydryl Compounds / Q000633:toxicity; D002164:Camphor / Q000031:analogs & derivatives / Q000633:toxicity; D002934:Cinnamates / Q000633:toxicity; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D005835:Genitalia / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D008297:Male; D010226:Parabens / Q000633:toxicity; D010636:Phenols / Q000633:toxicity; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects*; D000098826:Bisphenol A Compounds
chemical_list: D000082:Acetaminophen; D001559:Benzhydryl Compounds; D002164:Camphor; D002934:Cinnamates; D052244:Endocrine Disruptors; D010226:Parabens; D010636:Phenols; C038091:butylparaben; C118580:octylmethoxycinnamate; C038939:enzacamene; C006780:bisphenol A; D000098826:Bisphenol A Compounds