diisononyl-phthalate and Hypospadias

This study investigates possible effects of in utero exposure of rats to a low dose (125 mg/kg bw/day) and a high dose (750 mg/kg bw/day) of Diisononyl phthalate (DINP) during the masculinisation programming window (MPW) which is embryonic days 15.5-18.5 (e15.5 - e18.5). Dibutyl phthalate (DBP) was used at a high dose level (750 mg/kg bw/day) as an established positive control substance for anti-androgenic effects on the developing male reproductive tract. We focussed on the MPW and measured a multitude of biological endpoints at various life stages and applied state of the art histopathology staining techniques to refine the characterization of potential changes to the testis, beyond what is currently available with DINP. If DINP can mediate testicular dysgenesis (TDS) disorders, this exposure window would be sufficient to induce androgen impacts and alter male reproductive tract development as shown earlier in this validated experimental model with DBP. Overall, the results of this systematic comparison provide convincing evidence on the differences between the effects occurring with DBP and DINP. In contrast to what was seen with DBP, DINP did not cause cryptorchidism or hypospadias, had no effect on anogenital distance/anogenital index (AGD/AGi) and Leydig cell aggregates on e17.5 and e21.5 did not increase. With DINP no reduction of intratesticular testosterone, no effects on sperm motility and sperm count and no effect on adult testosterone or luteinizing hormone (LH) levels were seen. Our results demonstrate that DINP does not cause the adverse reproductive effects known to occur with DBP, a well-established endocrine disruptor.

Topics: Animals; Cryptorchidism; Dibutyl Phthalate; Dose-Response Relationship, Drug; Endocrine Disruptors; Female; Fetal Development; Gene Expression; Hypospadias; Leydig Cells; Male; Phthalic Acids; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sperm Motility; Spermatogenesis; Testis; Testosterone

Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to study prenatal di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) exposure in relation to cryptorchidism, hypospadias, and human fetal Leydig cell function.. We studied 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls. Second-trimester amniotic fluid samples were available from a Danish pregnancy-screening biobank (n = 25,105) covering 1980-1996. We assayed metabolites of DEHP and DiNP (n = 645) and steroid hormones (n = 545) by mass spectrometry. We assayed insulin-like factor 3 by immunoassay (n = 475) and analyzed data using linear or logistic regression.. Mono(2-ethyl-5-carboxypentyl) phthalate (5cx-MEPP, DEHP metabolite) was not consistently associated with cryptorchidism or hypospadias. However, we observed an 18% higher (95% confidence interval [CI] = 5%-33%) testosterone level, and a 41% lower (-56% to -21%) insulin-like factor 3 level in the highest 5cx-MEPP tertile compared with the lowest. Mono(4-methyl-7-carboxyheptyl) phthalate (7cx-MMeHP, DiNP metabolite) showed elevated odds ratio point estimates for having cryptorchidism (odds ratio = 1.28 [95% CI = 0.80 to 2.01]) and hypospadias (1.69 [0.78 to 3.67]), but was not consistently associated with the steroid hormones or insulin-like factor 3.. Data on the DEHP metabolite indicate possible interference with human male fetal gonadal function. Considering the DiNP metabolite, we cannot exclude (nor statistically confirm) an association with hypospadias and, less strongly, with cryptorchidism.

Topics: Adult; Amniotic Fluid; Case-Control Studies; Cryptorchidism; Denmark; Diethylhexyl Phthalate; Environmental Exposure; Female; Gonadal Steroid Hormones; Humans; Hydrocortisone; Hypospadias; Immunoassay; Infant, Newborn; Insulin; Leydig Cells; Linear Models; Logistic Models; Male; Mass Spectrometry; Phthalic Acids; Pregnancy; Proteins