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Endocrine disruptors and human reproductive failure: the in vitro effect of phthalates on human luteal cells

      Objective

      To evaluate the influence of phthalates on human luteal cell function.

      Design

      Laboratory study.

      Setting

      University hospital.

      Patient(s)

      Twenty-three normally menstruating patients in the midluteal phase.

      Intervention(s)

      Human luteal cells isolated from corpora lutea for primary cultures.

      Main Outcome Measure(s)

      Progesterone (P4) and prostaglandin release assayed by enzyme immunoassay, vascular endothelial growth factor (VEGF) secretion by enzyme-linked immunosorbent assay (ELISA), and VEGF mRNA expression by real-time polymerase chain reaction.

      Result(s)

      We investigated the effect of di(2-ethylhexyl)phthalate (DEHP), di-n-butyl phthalate (DBP), and butyl benzyl phthalate (BBP) on basal and hCG-induced progesterone (P4) release, as well as DEHP effect on the balance between prostaglandin (PG) E2, vascular endothelial growth factor (VEGF)-luteotrophic factors, and the luteolitic PGF2α in isolated human steroidogenc cells. Phthalates influence on VEGF expression has been also evaluated. DEHP, DBP, and BBP were able to reduce both basal and hCG-stimulated P4 as well as PGE2 release. PGF2α release was reduced after DEHP incubation. VEGF protein release was decreased by the incubation with the tested phthalates. VEGF mRNA expression was not affected by DEHP, DBP, and BBP. As expected, both hCG and cobalt chloride were able to induce P4 release and VEGF release and mRNA expression in human luteal cells respectively.

      Conclusion(s)

      The results show the ability of phthalates to affect luteal steroidogenesis as well as the balance between luteotrophic and luteolytic factors suggesting an interference of phthalates in human luteal function. These data may contribute to clarify the classically known impaired reproductive health observed after phthalates exposure.

      Key Words

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      References

        • Vandenberg L.N.
        • Maffini M.V.
        • Sonnenschein C.
        • Rubin B.S.
        • Soto A.M.
        Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption.
        Endocr Rev. 2009; 30: 75-95
        • Lovekamp-Swan T.
        • Davis B.J.
        Mechanisms of phthalate ester toxicity in the female reproductive system.
        Environ Health Perspect. 2003; 111: 139-145
        • Blount B.C.
        • Milgram K.E.
        • Silva M.J.
        • Malek N.A.
        • Reidy J.A.
        • Needham L.L.
        • et al.
        Quantitative detection of eight phthalate metabolites in human urine using HPLC-APCI-MS/MS.
        Anal Chem. 2000; 72: 4127-4134
        • Wittassek M.
        • Koch H.M.
        • Angerer J.
        • Bruning T.
        Assessing exposure to phthalates - the human biomonitoring approach.
        Mol Nutr Food Res. 2011; 55: 7-31
        • Schlumpf M.
        • Kypke K.
        • Wittassek M.
        • Angerer J.
        • Mascher H.
        • Mascher D.
        • et al.
        Exposure patterns of UV filters, fragrances, parabens, phthalates, organochlor pesticides, PBDEs, and PCBs in human milk: correlation of UV filters with use of cosmetics.
        Chemosphere. 2010; 81: 1171-1183
        • Dickson-Spillmann M.
        • Siegrist M.
        • Keller C.
        • Wormuth M.
        Phthalate exposure through food and consumers' risk perception of chemicals in food.
        Risk Anal. 2009; 29: 1170-1181
        • Petersen J.H.
        • Breindahl T.
        Plasticizers in total diet samples, baby food and infant formulae.
        Food Addit Contam. 2000; 17: 133-141
        • Kolpin D.W.
        • Furlong E.T.
        • Meyer M.T.
        • Thurman E.M.
        • Zaugg S.D.
        • Barber L.B.
        • et al.
        Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999–2000: a national reconnaissance.
        Environ Sci Technol. 2002; 36: 1202-1211
        • Bosnir J.
        • Puntaric D.
        • Skes I.
        • Klaric M.
        • Simic S.
        • Zoric I.
        Migration of phthalates from plastic products to model solutions.
        Coll Antropol. 2003; 27: 23-30
        • Ambruosi B.
        • Uranio M.F.
        • Sardanelli A.M.
        • Pocar P.
        • Martino N.A.
        • Paternoster M.S.
        • et al.
        In vitro acute exposure to DEHP affects oocyte meiotic maturation, energy and oxidative stress parameters in a large animal model.
        PLoS One. 2011; 6: e27452
        • Caserta D.
        • Mantovani A.
        • Marci R.
        • Fazi A.
        • Ciardo F.
        • La R.C.
        • et al.
        Environment and women's reproductive health.
        Hum Reprod Update. 2011; 17: 418-433
        • Gupta R.K.
        • Singh J.M.
        • Leslie T.C.
        • Meachum S.
        • Flaws J.A.
        • Yao H.H.
        Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro.
        Toxicol Appl Pharmacol. 2010; 242: 224-230
        • Snijder C.A.
        • te Velde E.
        • Roeleveld N.
        • Burdorf A.
        Occupational exposure to chemical substances and time to pregnancy: a systematic review.
        Hum Reprod Update. 2012; 18: 284-300
        • Aldyreva M.V.
        • Klimova T.S.
        • Iziumova A.S.
        • Timofeevskaia L.A.
        [The effect of phthalate plasticizers on the generative function].
        Gig Tr Prof Zabol. 1975; : 25-29
        • Zhang X.F.
        • Zhang L.J.
        • Li L.
        • Feng Y.N.
        • Chen B.
        • Ma J.M.
        • et al.
        Diethylhexyl phthalate exposure impairs follicular development and affects oocyte maturation in the mouse.
        Environ Mol Mutagen. 2013; 54: 354-361
        • Howdeshell K.L.
        • Rider C.V.
        • Wilson V.S.
        • Gray Jr., L.E.
        Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats.
        Environ Res. 2008; 108: 168-176
        • Tranfo G.
        • Caporossi L.
        • Paci E.
        • Aragona C.
        • Romanzi D.
        • De C.C.
        • et al.
        Urinary phthalate monoesters concentration in couples with infertility problems.
        Toxicol Lett. 2012; 213: 15-20
        • Guerra M.T.
        • Scarano W.R.
        • de Toledo F.C.
        • Franci J.A.
        • Kempinas W.G.
        Reproductive development and function of female rats exposed to di-eta-butyl-phthalate (DBP) in utero and during lactation.
        Reprod Toxicol. 2010; 29: 99-105
        • Lyche J.L.
        • Gutleb A.C.
        • Bergman A.
        • Eriksen G.S.
        • Murk A.J.
        • Ropstad E.
        • et al.
        Reproductive and developmental toxicity of phthalates.
        J Toxicol Environ Health B Crit Rev. 2009; 12: 225-249
        • Reddy B.S.
        • Rozati R.
        • Reddy B.V.
        • Raman N.V.
        Association of phthalate esters with endometriosis in Indian women.
        BJOG. 2006; 113: 515-520
        • Moral R.
        • Santucci-Pereira J.
        • Wang R.
        • Russo I.H.
        • Lamartiniere C.A.
        • Russo J.
        In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats.
        Environ Health. 2011; 10: 5
        • Arosh J.A.
        • Banu S.K.
        • Chapdelaine P.
        • Madore E.
        • Sirois J.
        • Fortier M.A.
        Prostaglandin biosynthesis, transport, and signaling in corpus luteum: a basis for autoregulation of luteal function.
        Endocrinology. 2004; 145: 2551-2560
        • Murphy B.D.
        Luteinization.
        in: Leung P.C.K. Adashi E.Y. The ovary. Elsevier Academic Press, San Diego2004: 185-199
        • Miceli F.
        • Tropea A.
        • Minici F.
        • Navarra P.
        • Lanzone A.
        • Apa R.
        Interleukin-1 beta stimulates progesterone production by in vitro human luteal cells: evidence of a mediatory role of prostaglandins.
        J Clin Endocrinol Metab. 2003; 88: 2690-2694
        • Apa R.
        • Miceli F.
        • Pierro E.
        • Minici F.
        • Navarra P.
        • Caruso A.
        • et al.
        Paracrine regulation of insulin-like growth factor I (IGF-I) an IGF-II on prostaglandins F2alpha and E2 synthesis by human corpus luteum in vitro: a possible balance of luteotropic and luteolytic effects.
        J Clin Endocrinol Metab. 1999; 84: 2507-2512
        • Krotz S.P.
        • Carson S.A.
        • Tomey C.
        • Buster J.E.
        Phthalates and bisphenol do not accumulate in human follicular fluid.
        J Assist Reprod Genet. 2012; 29: 773-777
        • Reinsberg J.
        • Wegener-Toper P.
        • van der Ven K.
        • van der Ven H.
        • Klingmueller D.
        Effect of mono-(2-ethylhexyl) phthalate on steroid production of human granulosa cells.
        Toxicol Appl Pharmacol. 2009; 239: 116-123
        • Dello Russo C.
        • Lisi L.
        • Tringali G.
        • Navarra P.
        Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation.
        Biochem Pharmacol. 2009; 78: 1242-1251
        • Lanzone A.
        • Di Simone N.
        • Castellani R.
        • Fulghesu A.M.
        • Caruso A.
        • Mancuso S.
        Human growth hormone enhances progesterone production by human luteal cells in vitro: evidence of a synergistic effect with human chorionic gonadotropin.
        Fertil Steril. 1992; 57: 92-96
        • Tropea A.
        • Tiberi F.
        • Minici F.
        • Orlando M.
        • Gangale M.F.
        • Romani F.
        • et al.
        Ghrelin affects the release of luteolytic and luteotropic factors in human luteal cells.
        J Clin Endocrinol Metab. 2007; 92: 3239-3245
        • Romani F.
        • Lanzone A.
        • Tropea A.
        • Familiari A.
        • Scarinci E.
        • Sali M.
        • et al.
        In vitro effect of unacylated ghrelin and obestatin on human luteal cell function.
        Fertil Steril. 2012; 97: 991-996
        • Tropea A.
        • Miceli F.
        • Minici F.
        • Tiberi F.
        • Orlando M.
        • Gangale M.F.
        • et al.
        Regulation of vascular endothelial growth factor synthesis and release by human luteal cells in vitro.
        J Clin Endocrinol Metab. 2006; 91: 2303-2309
        • Pollack G.M.
        • Li R.C.
        • Ermer J.C.
        • Shen D.D.
        Effects of route of administration and repetitive dosing on the disposition kinetics of di(2-ethylhexyl) phthalate and its mono-de-esterified metabolite in rats.
        Toxicol Appl Pharmacol. 1985; 79: 246-256
        • Davis B.J.
        • Weaver R.
        • Gaines L.J.
        • Heindel J.J.
        Mono-(2-ethylhexyl) phthalate suppresses estradiol production independent of FSH-cAMP stimulation in rat granulosa cells.
        Toxicol Appl Pharmacol. 1994; 128: 224-228
        • Craig Z.R.
        • Wang W.
        • Flaws J.A.
        Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling.
        Reproduction. 2011; 142: 633-646
        • Svechnikova I.
        • Svechnikov K.
        • Soder O.
        The influence of di-(2-ethylhexyl) phthalate on steroidogenesis by the ovarian granulosa cells of immature female rats.
        J Endocrinol. 2007; 194: 603-609
        • Buteau-Lozano H.
        • Velasco G.
        • Cristofari M.
        • Balaguer P.
        • Perrot-Applanat M.
        Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism.
        J Endocrinol. 2008; 196: 399-412
        • Neeman M.
        • Abramovitch R.
        • Schiffenbauer Y.S.
        • Tempel C.
        Regulation of angiogenesis by hypoxic stress: from solid tumours to the ovarian follicle.
        Int J Exp Pathol. 1997; 78: 57-70
        • Hanahan D.
        • Folkman J.
        Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
        Cell. 1996; 86: 353-364
        • Yoo P.S.
        • Mulkeen A.L.
        • Cha C.H.
        Post-transcriptional regulation of vascular endothelial growth factor: implications for tumor angiogenesis.
        World J Gastroenterol. 2006; 12: 4937-4942
        • Dickson S.E.
        • Bicknell R.
        • Fraser H.M.
        Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor.
        J Endocrinol. 2001; 168: 409-416
        • Fraser H.M.
        • Duncan W.C.
        SRB Reproduction, Fertility and Development Award Lecture 2008. Regulation and manipulation of angiogenesis in the ovary and endometrium.
        Reprod Fertil Dev. 2009; 21: 377-392
        • Cobellis L.
        • Latini G.
        • De F.C.
        • Razzi S.
        • Paris I.
        • Ruggieri F.
        • et al.
        High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis.
        Hum Reprod. 2003; 18: 1512-1515
        • Lovekamp T.N.
        • Davis B.J.
        Mono-(2-ethylhexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells.
        Toxicol Appl Pharmacol. 2001; 172: 217-224