NTP developmental and reproductive toxicity technical report on the modified one-generation study of bisphenol\sAF (CASRN 1478-61-1) administered in feed to Sprague Dawley (Hsd:Sprague Dawley(r) sD(r)) rats with prenatal, reproductive performance, and su / National Toxicology Program (U.S.).

Format:

Book

Author/Creator:

National Toxicology Program (U.S.), author, issuing body.

Language:

English

Subjects (All):

Nanostructured materials.

Nanoparticles.

Physical Description:

1 online resource

Other Title:

NTP developmental and reproductive toxicity technical report on the modified one-generation study of bisphenol\sAF

Place of Publication:

Research Triangle Park, North Carolina : National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services, 2022.

Summary:

MODIFIED ONE-GENERATION STUDY: F0\sdietary exposure began on gestation day (GD)\s6 and continued throughout the study. Biological samples were collected on GD 18 (maternal and fetal), on lactation day (LD) 4 (maternal), and on postnatal day (PND)\s4 (pup) to determine maternal transfer. At weaning on PND\s28, offspring were randomly assigned to the reproductive performance (1/sex/litter), prenatal (1/sex/litter), subchronic (1/sex/litter from 10\slitters), or biological sampling (6/sex for sample collection on PND\s28 to determine internal concentrations of BPAF and up to 12\sfemales for sample collection at vaginal opening) cohort. Upon sexual maturity, F1\smating and pregnancy indices were evaluated. In the prenatal cohort, F2\sprenatal development (litter size, fetal weight, and morphology) was assessed on GD\s21. In the reproductive performance cohort, littering indices and F2\sviability and growth were assessed until PND\s91. The likelihood of identifying potential BPAF-induced adverse effects and their similarity and magnitude--at any phase of growth or development--was increased by examining related endpoints in multiple pups within a litter throughout life, across cohorts, and across generations. In this study, dietary consumption of BPAF was associated with lower F0, F1, and F2\smean body weights. The lower F0\sfemale mean body weights and body weight gains during gestation were associated with a significant decrease in PND\s1 F1\spup weights (9% and 15% in the 1,125 and 3,750\sppm groups, respectively) that continued through PND\s98. Significant decreases in F2\smean body weights were also observed for 1,125\sppm male and female pups (12% on PND 28 for both males and females) through weaning, but only female postweaning mean body weights were significantly decreased through PND\s91 for both the 338 and 1,125\sppm groups. Several biochemical and hematological changes in the F1\sgeneration subchronic cohort were noted. BPAF exposure related changes included significant decreases in serum cholesterol concentrations in both sexes and in serum bile acid concentrations in males, while significant increases in serum triglyceride concentrations were noted in females. Hematological changes were limited to females and included significant decreases in erythrocyte count, hemoglobin concentration, and total white blood cell count. BPAF-related changes in reproductive performance were observed at all exposure concentrations. For the 3,750\sppm group, a complete absence of pregnant females in the F1\sgeneration resulted in only two concentration groups for evaluation in the F2 generation (338 and 1,125\sppm). The majority (89%) of females in the 3,750 ppm group were not cycling and were in persistent estrus. A slight but significant increase in gestation length for F0\sfemales and a significant decrease in F1\spup survival (PND\s1-4) were also attributed to BPAF exposure. Similar findings, although to a lesser extent, were observed at lower concentrations in the prenatal cohort and included a significant decrease in the number of F1\sfemales with live fetuses or live litters, number of corpora lutea, and number of implantation sites in the 1,125\sppm group, which were associated with a significant increase in pre- and postimplantation loss values. Significant decreases in the number of corpora lutea and implantation sites were also noted for the prenatal cohort females in the 338\sppm group. Changes in organ weights were also observed in the F1\sgeneration. In the subchronic cohort, significant increases in the relative weights of the lungs, adrenal glands, and thyroid gland were noted in the 3,750\sppm F1\smales. Significant decreases in relative weights for the liver and kidney (left) were also observed at 3,750\sppm for F1 males and microscopic findings were observed in the male kidney (mineral lesions along the junction of the cortex and medulla). In F1\smales, lower absolute weights of the dorsolateral prostate, ventral prostate, and seminal vesicles with coagulating glands were observed in the 1,125 and 3,750\sppm groups and of the Cowper's gland and levator ani/bulbocavernosus muscle (LABC) in the 3,750\sppm group. The organ weight changes in the 3,750\sppm group were more than the magnitude of the reductions in body weight and, along with histopathology observations of hypoplasia, indicated a potential direct BPAF-mediated suppression of maturation of these tissues. F2\smales exhibited similar findings in the same reproductive tissues as F1\smales in the 338 and 1,125\sppm groups. Changes in reproductive organ weights that appeared secondary to the effect of BPAF on body weight were limited to lower absolute weights of the testes, epididymides, and preputial glands in all three F1\sexposed groups. The lower testes weights may also be due to direct (germinal epithelium degeneration and Leydig cell atrophy) effects of BPAF exposure. Changes in reproductive organ weights that appear to be secondary to the effect of BPAF on body weight for the F2 exposed males were limited to the testes and epididymides. Histopathology was not performed on the F2\sgeneration. BPAF-related changes in andrology parameters were noted in both F1 and F2 males. In F1\sfemales, reproductive toxicity associated with exposure to BPAF included significant decreases in absolute ovarian and uterus/cervix/vagina weights, with gross observations of reduced size and hypoplasia in the 3,750\sppm group. In the subchronic cohort, significant increases in the relative weights of the thyroid gland and liver were noted in the 3,750 ppm F1 females. Significant decreases in absolute ovarian weights were also observed in the 338 and 1,125\sppm F2\sfemales. The magnitude of the reduction in weights of the ovaries in the 1,125\sppm group was more than the magnitude of the reduction in body weight, suggesting a direct BPAF-mediated suppression of maturation of this tissue. BPAF-related changes consistent with impaired development include lower mean body weights for all generations, including fetal or pup weights and reduced litter sizes, as well as impacts on fetal parameters and select developmental markers. Developmental landmarks impacted by BPAF exposure included time to vaginal opening (VO), testicular descent, and balanopreputial separation (BPS). No impacts on anogenital distance or areolae and nipple retention were observed in this study. The time to VO was significantly accelerated in all BPAF-exposed groups for both the F1\sand F2\sgenerations at all exposure concentrations. The mean day of testicular descent was not affected in the F1\sgeneration, although one male in the 1,125\sppm group and 11\smales in the 3,750\sppm group did not attain testicular descent by study termination; however, the mean day of testicular descent was significantly delayed by approximately 2\sdays for the F2\soffspring in the 1,125\sppm group. In addition, 10 F1\smales in the 3,750\sppm group did not attain BPS. The time to BPS was significantly delayed in both the F1\sand F2\soffspring in the 1,125 and 3,750\sppm groups for the F1\sgeneration and the 1,125\sppm group for the F2\sgeneration. BPAF exposure resulted in fetal malformations of the penis and vagina in two F1\smales and three F1\sfemales in the 3,750\sppm group. Additional findings were limited to an increase in the incidence of dilated and/or misshapen lateral ventricle (brain) in the 1,125\sppm group, which NTP has not recorded in its previous studies, and increases in the incidences of rudimentary and full lumbar I (L1) ribs in the 338\sppm group and rudimentary L1 ribs in the 1,125\sppm group for the prenatal cohort. These last findings were outside the NTP historical control ranges; however, the lack of an exposure-related response impedes a more thorough assessment to determine if they may have been related to BPAF exposure. (This is an abridged version of the abstract. Go to the Abstract page to see the full text and summary table.).

Contents:

Foreword

Tables

Figures

About This Report

Explanation of Levels of Evidence for Reproductive Toxicity

Explanation of Levels of Evidence for Developmental Toxicity

Peer Review

Publication Details

Acknowledgments

Abstract

Introduction

Materials and Methods.

Notes:

Description based on publisher supplied metadata and other sources.