TY - JOUR
TI - Gestational exposure to an epidemiologically defined mixture of phthalates leads to gonadal dysfunction in mouse offspring of both sexes
AU - Repouskou, A.
AU - Panagiotidou, E.
AU - Panagopoulou, L.
AU - Bisting, P.L.
AU - Tuck, A.R.
AU - Sjödin, M.O.D.
AU - Lindberg, J.
AU - Bozas, E.
AU - Rüegg, J.
AU - Gennings, C.
AU - Bornehag, C.-G.
AU - Damdimopoulou, P.
AU - Stamatakis, A.
AU - Kitraki, E.
JO - Scientific Reports
PY - 2019
VL - 9
TODO - 1
SP - null
PB - Nature Publishing Group
SN - 2045-2322
TODO - 10.1038/s41598-019-42377-6
TODO - aromatase;  Cyp19a1 protein, mouse;  estradiol;  follitropin receptor;  forkhead box protein L2;  Foxl2 protein, mouse;  LHCGR protein, mouse;  luteinizing hormone receptor;  mono-(2-ethylhexyl)phthalate;  mono-benzyl phthalate;  monoisononylphthalate;  phthalic acid bis(2 ethylhexyl) ester;  phthalic acid derivative;  phthalic acid dibutyl ester;  steroid 17alpha monooxygenase;  testosterone, animal;  blood;  C57BL mouse;  drug effect;  female;  first trimester pregnancy;  gene expression;  genetics;  human;  male;  maternal exposure;  metabolism;  mouse;  organ size;  ovary;  pathophysiology;  pollutant;  pregnancy;  prenatal exposure;  testis;  toxicity, Animals;  Aromatase;  Dibutyl Phthalate;  Diethylhexyl Phthalate;  Environmental Pollutants;  Estradiol;  Female;  Forkhead Box Protein L2;  Gene Expression;  Humans;  Male;  Maternal Exposure;  Mice;  Mice, Inbred C57BL;  Organ Size;  Ovary;  Phthalic Acids;  Pregnancy;  Pregnancy Trimester, First;  Prenatal Exposure Delayed Effects;  Receptors, FSH;  Receptors, LH;  Steroid 17-alpha-Hydroxylase;  Testis;  Testosterone
TODO - The increasing concern for the reproductive toxicity of abundantly used phthalates requires reliable tools for exposure risk assessment to mixtures of chemicals, based on real life human exposure and disorder-associated epidemiological evidence. We herein used a mixture of four phthalate monoesters (33% mono-butyl phthalate, 16% mono-benzyl phthalate, 21% mono-ethyl hexyl phthalate, and 30% mono-isononyl phthalate), detected in 1 st trimester urine of 194 pregnant women and identified as bad actors for a shorter anogenital distance (AGD) in their baby boys. Mice were treated with 0, 0.26, 2.6 and 13 mg/kg/d of the mixture, corresponding to 0x, 10x, 100x, 500x levels detected in the pregnant women. Adverse outcomes detected in the reproductive system of the offspring in pre-puberty and adulthood included reduced AGD index and gonadal weight, changes in gonadal histology and altered expression of key regulators of gonadal growth and steroidogenesis. Most aberrations were apparent in both sexes, though more pronounced in males, and exhibited a non-monotonic pattern. The phthalate mixture directly affected expression of steroidogenesis as demonstrated in a relevant in vitro model. The detected adversities at exposures close to the levels detected in pregnant women, raise concern on the existing safety limits for early-life human exposures and emphasizes the need for re-evaluation of the exposure risk. © 2019, The Author(s).
ER -