title: Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice.
abstract: Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring. In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant.
authors.affiliation: Department of Veterinary Medicine, University of Milan, 20133 Milan, Italy. Electronic address: paola.pocar@unimi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Pocar
authors.affiliation: Department of Veterinary Medicine, University of Milan, 20133 Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Fiandanese
authors.affiliation: Department of Veterinary Medicine, University of Milan, 20133 Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Berrini
authors.affiliation: Department of Veterinary Medicine, University of Milan, 20133 Milan, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Secchi
authors.affiliation: Department of Veterinary Medicine, University of Milan, 20133 Milan, Italy.
authors.forename: Vitaliano
authors.initials: V
authors.lastname: Borromeo
mesh_terms: D000818:Animals; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D005854:Germ Cells / Q000187:drug effects* / Q000502:physiology; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D006080:Ovarian Follicle / Q000187:drug effects / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000503:physiopathology; D012098:Reproduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D052244:Endocrine Disruptors; D004051:Diethylhexyl Phthalate
keywords: Di(2-ethylhexyl)phthalate (DEHP); Maternal exposure; Mouse; Ovary; Reproductive toxicity; Transgenerational