Effects of bisphenol A on incidence and severity of cardiac lesions in the NCTR-Sprague-Dawley rat: A CLARITY-BPA study

Abstract

The goal of this study was to determine whether bisphenol A (BPA) had adverse effects indicative of cardiac toxicity. As part of the “Consortium Linking Academic and Regulatory Insights on BPA Toxicity” (CLARITY-BPA), study dams and offspring were exposed by daily gavage to five doses of BPA ranging from 2.5 to 25000 μg/kg/day, 0.05 or 0.5 μg/kg/day 17α-ethinyl-estradiol (EE) or 0.3% carboxymethylcellulose vehicle. Exposure-related effects were analyzed in isolated hearts by quantitative morphometry and histopathology. No dose-related changes in body weight were detected. Across all exposure groups including vehicle controls, body weight of continuously dosed males was reduced compared to males dosed only until PND21. Heart weight was increased only in females exposed to EE, and consistent alterations in LV wall thickness were not observed. Exposure-related changes in collagen accumulation were minor and limited to highest EE exposure groups with increased collagen accumulation in PND21 males. Decreased collagen was observed in hearts of BPA or EE exposed females at PND90 and PND180. In BPA or EE treated females cardiomyopathy incidence and severity was significantly increased compared to control females at PND21 with myocardial degeneration observed in both males and females at PND21 and PND90.

CLARITY‐BPA academic laboratory studies identify consistent low‐dose Bisphenol A effects on multiple organ systems

“…Previous studies had not analysed PCM lesions in hearts of young animals. In the CLARITY‐BPA study, a remarkable abundance of early PCM lesions was detected in the hearts of most control and exposed animals analysed at PND21 . Consistent with PCM found in adults, the lesion incidence and severity were greater in control males than in females.…”

“…In BPA‐ or EE‐treated females at PND21, cardiomyopathy incidence was increased compared to control females and a significant increase in severity was found for 2.5, 250 or 25 000 μg BPA/kg BW/d and both EE groups. In a male exposed to 250 μg BPA/kg BW/d and a female from each of the two lowest BPA dose groups (2.5 and 25 μg/kg BW/d), a diffuse degeneration phenotype involving much of the myocardium was also observed . This high level of cardiac pathology across much of the myocardium is an accepted indication of exposure‐related cardiotoxicity …”

“…The published finding analysing cardiac effects in CLARITY‐BPA NCTR Sprague‐Dawley rat hearts found limited evidence of BPA or EE alterations on gross cardiac end‐points related to hypertrophy. While alterations in LV wall thickness were not observed at any dose in either sex, a significant decrease in heart weight and heart weight normalized to body‐weight was observed in females exposed to 2.5 μg/kg BW/d BPA, a finding consistent with previous findings in mice .…”

“…At PND90 and 6 months, cardiomyopathy in both males and females was observed in 100% of control samples from both the stop dose and the continuous dose arms of the CLARITY‐BPA study . At PND90, the diffuse degeneration phenotype was again observed in males and females from the continuous (males: BPA 25, 250, 25 000; EE 0.5 μg/kg BW/d; females: BPA 2.5, 25; EE 0.05, 0.5 μg/kg BW/d) and stop dose (males: BPA 250, 25 000; EE 0.05, 0.5 μg/kg BW/d; Females 250 μg/kg BW/d) exposure groups.…”

Effects of perinatal bisphenol A exposure on the volume of sexually-dimorphic nuclei of juvenile rats: A CLARITY-BPA consortium study

“…Collectively all have shown sporadic and generally modest effects of BPA on the brain and behavior, cardiac endpoints, and female ovarian follicle numbers and sex steroid levels (Arambula et al, 2016; Gear et al, 2017; Johnson et al, 2015; Patel et al, 2017; Rebuli et al, 2015). Significantly, the observed increase in female AVPV volume occurred at the same doses reported to cause effects in other CLARITY-BPA studies.…”