Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats

Christiansen, Sofie; Boberg, Julie; Axelstad, Marta; Dalgaard, Majken; Vinggaard, Anne Marie; Metzdorff, Stine Broeng; Hass, Ulla

doi:10.1016/j.reprotox.2010.04.005

Cited by 131 publications

(70 citation statements)

References 40 publications

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“…Reduced AGD in male rats is usually a sign of antiandrogenic exposure during sexual development. When exposed to potent anti-androgens, AGDs in the male rodents are usually reduced in a dose-related manner, and for some chemicals, such as certain drugs or pesticides, perinatal exposure can even lead to males having female-like AGDs , Parks et al 2000, Christiansen et al 2010. However, other anti-androgenic chemicals show more shallow dose-response curves.…”

Section: Discussionmentioning

confidence: 99%

Low-dose effects of bisphenol A on early sexual development in male and female rats

Christiansen¹,

Axelstad²,

Boberg³

et al. 2014

Reproduction

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Bisphenol A (BPA) is widely detected in human urine and blood. BPA has been reported to impair many endpoints for reproductive and neurological development; however, it is controversial whether BPA has effects in the microgram per kilogram dose range. The aim of the current study was to examine the influence of BPA on early sexual development in male and female rats at dose levels covering both regulatory no observed adverse effect levels (NOAELs) (5 and 50 mg/kg bw per day) as well as doses in the microgram per kilogram dose range (0.025 and 0.25 mg/kg bw per day). Time-mated Wistar rats (nZ22) were gavaged during pregnancy and lactation from gestation day 7 to pup day 22 with 0, 0.025, 0.25, 5 or 50 mg/kg bw per day BPA. From 0.250 mg/kg and above, male anogenital distance (AGD) was significantly decreased, whereas decreased female AGD was seen from 0.025 mg/kg bw per day and above. Moreover, the incidence of nipple retention in males appeared to increase dose relatedly and the increase was statistically significant at 50 mg/kg per day. No significant changes in reproductive organ weights in the 16-day-old males and females and no signs of maternal toxicity were seen. The decreased AGD at birth in both sexes indicates effects on prenatal sexual development and provides new evidence of low-dose adverse effects of BPA in rats in the microgram per kilogram dose range. The NOAEL in this study is clearly below 5 mg/kg for BPA, which is used as the basis for establishment of the current tolerable daily intake (TDI) by EFSA; thus a reconsideration of the current TDI of BPA appears warranted.

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Section: Discussionmentioning

confidence: 99%

Low-dose effects of bisphenol A on early sexual development in male and female rats

Christiansen¹,

Axelstad²,

Boberg³

et al. 2014

Reproduction

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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%

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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“…A number of studies in rats are not suitable for the evaluation of developmental toxicity for the same reasons Christiansen et al 2010;Grande et al 2006;Wei et al 2012). Prenatal toxicity studies published since the 2002 documentation (documentation "Di(2-ethylhexyl)phthalate (DEHP)" 2009) revealed effects on the testes in rats on day 20 of gestation induced by in utero exposure to DEHP at 250 mg/kg body weight and day and above.…”

Section: Discussionmentioning

confidence: 99%

“…No maternal toxicity was observed up to doses of 900 mg/kg body weight and day (Christiansen et al 2010). According to OECD Test Guideline 414, the adrenals are weighed on postnatal day 16 and the accuracy depends on the experience of the staff in dealing with the surrounding connective tissue, which can account for up to 10% of the weight.…”

Section: Prenatal and Postnatal Exposure Up To The End Of Lactation Ratsmentioning

confidence: 91%

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

Hartwig

Arand²

2017

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the developmental toxicity of di(2‐ethylhexyl) phthalate (DEHP) [117‐81‐7]. In 2014, the maximum concentration at the work place (MAK value) of DEHP has been set to 2 mgm for the inhalable fraction. In some studies, a correlation between prenatal DEHP exposure and effects on anogenital distance of male newborns, birth weight and pregnancy duration in humans are found, however, the results are not consistent. Teratogenicity is observed in rats only at maternally toxic doses of 1000 mg/kg bw and day and above, in mice at 91 mg/kg bw and day. NOAELs for teratogenicity are 200 mg/kg bw and day for rats and 44 mg/kg body weight and day for mice, the latter corresponding to 29 mg/m 3 after scaling to a concentration at the work place. In contrast to mouse and marmoset the rat is very sensitive to DEHP effects on the male reproductive organs. From a three generation study the Commission deduces a NOAEL for pre‐ and postnatal developmental toxicity to the male reproductive organs and for fetotoxicity of 46 mg/kg bw and day for rats, corresponding to 54 mg/m 3 after scaling to a concentration at the work place. The reported effects, small testes, reduced absolute weights of testis and epididymis, are considered by the Commission as not being adverse because they do not show correlating consequences for the next generation or dose‐response relationship and changes in relative organ weights and histopathological correlates are not observed. After in utero exposure, germ cell organization, mRNA expression and protein level of StAR („steroidogenic acute regulatory protein“) in testes are affected at 100 mg/kg bw and day and above. These effects resulted in a NOAEL for prenatal developmental effects of the male reproductive organs of 30 mg/kg bw and day for rats, corresponding to 35 mg/m 3 . For mice in prenatal developmental studies a NOAEL for fetotoxicity as well as prenatal developmental toxicity of 48 mg/kg bw and day is derived, corresponding to 32 mg/m 3 . Damage to the embryo or foetus is unlikely when the MAK value is observed and DEHP is classified in Pregnancy Risk Group C.

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Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats

Cited by 131 publications

References 40 publications

Low-dose effects of bisphenol A on early sexual development in male and female rats

Low-dose effects of bisphenol A on early sexual development in male and female rats

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

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

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