Reproductive and behavioral effects of diisononyl phthalate (DINP) in perinatally exposed rats

Boberg, Julie; Christiansen, Sofie; Axelstad, Marta; Kledal, Thuri Seidler; Vinggaard, Anne Marie; Dalgaard, Majken; Nellemann, Christine; Hass, Ulla

doi:10.1016/j.reprotox.2010.11.001

Cited by 142 publications

(129 citation statements)

References 47 publications

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“…There are several known mechanisms of action for these effects on the male rat, such as the inhibition of testosterone synthesis (Auharek et al 2010, Christiansen et al 2010, MacLeod et al 2010, Boberg et al 2011, inhibition of E 2 synthesis in granulosa cells (Reinsberg et al 2009) as well as inhibition of aromatase activity (van Meeuwen et al 2008), prostaglandin synthesis (Kristensen et al 2011) and possibly effects via inhibition of the thyroid axis (Meeker & Ferguson 2011). This makes the interpretation of in vivo effects in humans very complex.…”

Section: Phthalates and Female Reproductive Developmentmentioning

confidence: 99%

“…Phthalates may exert anti-androgenic actions by interfering with steroidogenesis (Auharek et al 2010, Christiansen et al 2010, MacLeod et al 2010, Boberg et al 2011 and have been associated with a decrease in infant testosterone concentrations and an increase in luteinising hormone and sex hormone binding globulin (SHBG) levels (Main et al 2006a). Evidence for the reproductive effect of antenatal exposure to phthalates in humans is still sparse (Jurewicz & Hanke 2011).…”

Section: Introductionmentioning

confidence: 99%

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The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study

Hart¹,

Doherty²,

Frederiksen³

et al. 2014

Reproduction

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We hypothesised that antenatal exposure to ubiquitous phthalates may lead to an earlier menarche and a lower prevalence of polycystic ovarian syndrome (PCOS) and polycystic ovarian morphology (PCO) in adolescence. The Western Australian Pregnancy Cohort (Raine) Study recruited 3000 women at 18 weeks of gestation in 1989-1991, 1377 had antenatal serum stored without thawing at K80 8C. An unselected subset was evaluated in the early follicular phase for PCO and PCOS by ultrasound and serum evaluation in adolescence. Serum was analysed for anti-Mü llerian hormone (AMH), inhibin B, sex hormone binding globulin (SHBG), testosterone, androstenedione and DHEAS. Four hundred microlitres of the frozen maternal serum underwent isotope-diluted liquid chromatography-tandem mass spectrometry, with preceding enzymatic deconjugation followed by solid-phase extraction to determine phthalate exposure. Two hundred and forty four girls attended assessment and most common phthalate metabolites were detectable in the majority of the 123 samples available. Several phthalates were negatively associated with maternal SHBG, and associations with maternal androgens were less consistent. The sum of the metabolites of di-(2-ethylhexyl) phthalate was associated with a non-significant tendency towards an earlier age at menarche (PZ0.069). Uterine volume was positively associated with mono-(carboxy-iso-octyl) phthalate (PZ0.018). Exposure to monoethyl phthalate (MEP) and the sum of all phthalate metabolites (Sall phth.m) were protective against PCOS in adolescence (PZ0.001 and PZ0.005 respectively). There were negative associations of MEP with PCO (PZ0.022) and of MEP with serum AMH (PZ0.031). Consequently, our data suggest that antenatal exposure to environmental phthalates may be associated with oestrogenic and/or anti-androgenic reproductive effects in adolescent girls.

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Section: Phthalates and Female Reproductive Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study

Hart¹,

Doherty²,

Frederiksen³

et al. 2014

Reproduction

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“…DiNP also caused skeletal and urinary system developmental toxicity in rats exposed prenatally to DiNP at maternally toxic doses (Hellwig et al 1997;Waterman et al 1999). Studies of fetal testicular testosterone production and other reproductive endpoints from prenatal DiNP exposure in rats have produced conflicting results, possibly due to experimental differences in the route, timing, and levels of dosing (Boberg et al 2011;Adamsson et al 2009;Borch et al 2004;Masutomi et al 2003;Waterman et al 2000;Gray et al 2000). Where reproductive effects have been observed, the potency of DiNP appeared to be about an order of magnitude less than DEHP (Gray et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Occupational exposure to diisononyl phthalate (DiNP) in polyvinyl chloride processing operations

Hines

Hopf

Deddens

et al. 2011

Int Arch Occup Environ Health

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“…This has been described as the "phthalate syndrome" in rats and demonstrates that in utero exposure to antiandrogenic phthalates during the male programming window exert a direct testicular toxic effect leading to reduced testosterone production and conditions such as hypospadias and cryptorchidism (18)(19)(20). Diisononyl phthalate is a known replacement for DEHP and has also been found to have antiandrogenic properties in utero in rodent models (18,21). In humans, phthalate exposure during pregnancy is associated with a number of infant and child developmental endpoints that are androgen mediated, including reduced anogenital distance (AGD) (22,23), a measure of fetal androgen exposure, and changes in sex-specific behavior (24,25).…”

mentioning

confidence: 99%

Early Prenatal Phthalate Exposure, Sex Steroid Hormones, and Birth Outcomes

Sathyanarayana

Butts

Wang

et al. 2017

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context: Adequate sex steroid hormone concentrations are essential for normal fetal genital development in early pregnancy. Our previous study demonstrated an inverse relationship between third-trimester di-2-ethyl hexyl phthalate exposure and total testosterone (TT) concentrations. Here, we examine earlypregnancy phthalates, sex steroid hormone concentrations, and newborn reproductive outcomes. Design:We examined associations between urinary phthalate metabolite concentrations in early pregnancy and serum free testosterone (FT), TT, estrone (E1), and estradiol (E2) in 591 woman/infant dyads in The Infant Development and Environment Study; we also examined relationships between hormones and newborn genital outcomes using multiple regression models with covariate adjustment.Results: E1 and E2 concentrations were 15% to 30% higher in relation to 1-unit increases in log monoisobutyl phthalate (MiBP), mono-2-ethyl hexyl phthalate, and mono-2-ethyl-5-oxy-hexyl phthalate concentrations, and E2 was 15% higher in relation to increased log monobenzyl phthalate (MBzP). FT concentrations were 12% lower in relation to 1-unit increases in log mono(carboxynonyl) phthalate (MCNP) and mono-2-ethyl-5-carboxypentyl phthalate concentrations. Higher maternal FT was associated with a 25% lower prevalence of having a male genital abnormality at birth. Conclusions:The positive relationships between MiBP, MBzP, and DEHP metabolites and E1/E2 are unique and suggest a positive estrogenic effect in early pregnancy. The inverse relationship between MCNP and DEHP metabolites and serum FT supports previous work examining phthalate/testosterone relationships later in pregnancy. Higher FT in relation to a 25% lower prevalence of male genital abnormalities confirms the importance of testosterone in early fetal development. Abbreviations: AGD, anogenital distance; AGD AC , anoclitoral distance; AGD AF , anofourchette distance; AGD AP , anopenile distance; AGD AS , anoscrotal distance; BBzP, benzyl butyl phthalate; CDC, Centers for Disease Control and Prevention; CI, confidence interval; DBP, dibutyl phthalate; DEHP, di-2-ethyl hexyl phthalate; EDC, endocrine-disrupting chemical; FT, free testosterone; HPLC, high-performance liquid chromatography; LC, liquid chromatography; LOD, limit of detection; MBP, monobutyl phthalate; MBzP, monobenzyl phthalate; MCNP, mono(carboxynonyl) phthalate; MCOP, mono(carboxy-isooctyl) phthalate; MECPP, mono-2-ethyl-5-carboxypentyl phthalate; MEHP, mono-2-ethylhexyl phthalate; MEHHP, mono-2-ethyl-5-hydroxy-hexyl phthalate; MEOHP, mono-2-ethyl-5-oxy-hexyl phthalate; MEP, monoethyl phthalate; MiBP, monoisobutyl phthalate; MS/MS, tandem mass spectrometry; SD, standard deviation; SHBG, sex hormone-binding globulin; TIDES, The Infant Development and the Environment Study; TT, total testosterone. 1870https://academic.oup.com/jcem

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Reproductive and behavioral effects of diisononyl phthalate (DINP) in perinatally exposed rats

Cited by 142 publications

References 47 publications

The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study

The influence of antenatal exposure to phthalates on subsequent female reproductive development in adolescence: a pilot study

Occupational exposure to diisononyl phthalate (DiNP) in polyvinyl chloride processing operations

Early Prenatal Phthalate Exposure, Sex Steroid Hormones, and Birth Outcomes

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