Three-Generation Reproductive Toxicity Study of Dietary Bisphenol A in CD Sprague-Dawley Rats

Abstract

Bisphenol A (BPA) was evaluated at concentrations of 0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm ( approximately 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg/day of BPA) administered in the diet ad libitum to 30 CD((R)) Sprague-Dawley rats/sex/dose for 3 offspring generations, 1 litter/generation, through F3 adults. Adult systemic toxicity at 750 and 7500 ppm in all generations included: reduced body weights and body weight gains, reduced absolute and increased relative weanling and adult organ weights (liver, kidneys, adrenals, spleen, pituitary, and brain), and female slight/mild renal and hepatic pathology at 7500 ppm. Reproductive organ histopathology and function were unaffected. Ovarian weights as well as total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD). Mating, fertility, gestational indices; ovarian primordial follicle counts; estrous cyclicity; precoital interval; gestational length; offspring sex ratios; postnatal survival; nipple/areolae retention in preweanling males; epididymal sperm number, motility, morphology; daily sperm production (DSP), and efficiency of DSP were all unaffected. At 7500 ppm, vaginal patency (VP) and preputial separation (PPS) were delayed in F1, F2, and F3 offspring, associated with reduced body weights. Anogenital distance (AGD) on PND 0 was unaffected for F2 and F3 males and F3 females (F2 female AGD was increased at some doses, not at 7500 ppm, and was considered not biologically or toxicologically relevant). Adult systemic no observed adverse effect level (NOAEL) = 75 ppm (5 mg/kg/day); reproductive and postnatal NOAELs = 750 ppm (50 mg/kg/day). There were no treatment-related effects in the low-dose region (0.001-5 mg/kg/day) on any parameters and no evidence of nonmonotonic dose-response curves across generations for either sex. BPA should not be considered a selective reproductive toxicant, based on the results of this study.

The OECD program to validate the rat uterotrophic bioassay. Phase 2: dose-response studies.

“…BPA was negative at 200 mg/kg/day in all laboratories and was positive over a range of 375-1000 mg/kg/day. This compares favorably with the absence of estrogen-mediated effects at doses up to 500 mg/kg/day, as well in the controversial low-dose range in two multigeneration studies (Ema et al 2001;Tyl et al 2002). The GN and MX uterotrophic results in protocol A are also consistent when compared with available developmental and other studies (Casanova et al 1999;Chapin et al 1997;Newbold et al 2001).…”

The OECD program to validate the rat uterotrophic bioassay: an overview.

“…Phase 2 was conducted with compounds with weak agonists that likely represented target compounds of regulatory interest. To assess the predictivity of the uterotrophic bioassay, the weak agonists were selected because of the availability of reproductive and developmental studies with a battery of estrogen-sensitive end points (Chapin et al 1999;Tyl et al 2002). The chemicals were also selected with a range of potencies and different metabolic and pharmacokinetic properties in mind.…”

Comparative study of estrogenic potencies of estradiol, tamoxifen, bisphenol-A and resveratrol with two in vitro bioassays

“…Many chemicals in surface waters and sediments have recently been discovered to have estrogenic/anti-estrogenic activity in vitro (Chapin et al, 1999;Delclos et al, 2001;Nagao et al, 2001;Ema et al, 2001;Tyl et al, 1999Tyl et al, , 2002. Among these compounds are natural and synthetic phytoestrogen and a variety of industrial chemicals (Colburn et al, 1996;Matthiesen et al, 1996).…”