Reproductive toxicity and pharmacokinetics of di‐n‐butyl phthalate (DBP) following dietary exposure of pregnant rats

Abstract

Most rodent developmental toxicity studies of dibutylphthalate (DBP) have relied on bolus gavage dosing. This study characterized the developmental toxicity of dietary DBP. Pregnant CD rats were given nominal doses of 0, 100, or 500 mg DBP/kg/day in diet (actual intake 0, 112, and 582 mg/kg/day) from gestational day (GD) 12 through the morning of GD 19. Rats were killed 4 or 24 hr thereafter. DBP dietary exposure resulted in significant dose-dependent reductions in testicular mRNA concentration of scavenger receptor class B, member 1; steroidogenic acute regulatory protein; cytochrome P450, family 11, subfamily a, polypeptide 1; and cytochrome P450 family 17, subfamily a, polypeptide 1. These effects were most pronounced 4 hr after the end of exposure. Testicular testosterone was reduced 24 hr post-exposure in both DBP dose groups and 4 hr after termination of the 500-mg DBP/kg/day exposure. Maternal exposure to 500 mg DBP/kg/day induced a significant reduction in male offspring's anogenital distance indicating in utero disruption of androgen function. Leydig cell aggregates, increased cord diameters, and multinucleated gonocytes were present in DBP-treated rats. Monobutyl phthalate, the developmentally toxic metabolite of DBP, and its glucuronide conjugate were found in maternal and fetal plasma, amniotic fluid, and maternal urine. Our results, when compared to previously conducted gavage studies, indicate that approximately equal doses of oral DBP exposure of pregnant rats, from diet or gavage, result in similar responses in male offspring.

Reproductive and developmental effects of phthalate diesters in females

“…Other groups, however, have reported no effect on pregnancy in rats after doses of 500 mg/kg/d (Barlow & Foster, 2003; Carruthers & Foster, 2005; Ema et al, 1993a; Ema 2002; Fisher et al, 2003; Jiang et al, 2007; Mylchreest et al, 2000, 1998; Struve et al, 2009). One study examining a lower dose of DBP (100 mg/kg/d by gavage GD12-PND21) reported no effects on pregnancy outcomes including maternal weight, the number of implantation sites, serum progesterone and fertility of the female Wistar rats exposed during gestation (Guerra et al, 2010).…”

“…One study examining a lower dose of DBP (100 mg/kg/d by gavage GD12-PND21) reported no effects on pregnancy outcomes including maternal weight, the number of implantation sites, serum progesterone and fertility of the female Wistar rats exposed during gestation (Guerra et al, 2010). Overall, the studies which examined both the health of the pregnant dam and the reproductive health of the male pups generally found that the doses needed to affect the dam were higher than the doses that affected the male pups (Barlow & Foster, 2003; Carruthers & Foster, 2005; Ema & Miyawaki, 2001a; Fisher et al, 2003; Jiang et al, 2007; Lee et al, 2004; Mylchreest et al, 1998, 2000; Salazar et al, 2004; Struve et al, 2009; Zhang et al, 2004). …”

Man is not a big rat: concerns with traditional human risk assessment of phthalates based on their anti-androgenic effects observed in the rat foetus

“…Exposure to phthalates during foetal life causes many masculinization defects in the rat [16, 20, 43, 59, 80–88]. Specifically, phthalates induce hypospadias, cryptorchidism, gubernaculum alterations, defects in differentiation or growth of epididymis, seminal vesicles, deferent ducts, prostate, levator ani and bulbocavernosus muscles, Cowper’s glands, and reduced AGD.…”

Couples' urinary bisphenol A and phthalate metabolite concentrations and the secondary sex ratio

“…Previous studies have demonstrated that DBP, a substitute for DiBP with similar properties, and BzBP may produce reproductive and developmental toxicity, with the possibility of species-related differences (McKee et al, 2004). In multi-generation rodent studies, dietary exposure to DBP or BzBP resulted in a decrease in serum testosterone level in the parent animals and reduced anogenital distance and undescended testes in the male offspring (Kavlock et al, 2002; Struve et al, 2009; Tyl et al, 2004). These genital morphological changes have been also revealed in boys whose mothers had elevated prenatal phthalate exposure (Swan et al, 2005).…”