Table 5.
Comparison of outcomes from CLARITY-BPA with prior academic studies.
| Organ | Outcome in CLARITY-BPA | Outcome in prior studies | Comparison |
|---|---|---|---|
| Prostate | No prostate pathology (in unstimulated males). | No prostate pathology (in unstimulated males) | Similar to our prior studies, BPA alone was insufficient to induce prostate pathology. |
| Severity of PIN lesions in lateral prostate after adult T + E treatment (increased in 2.5, 250, 25,000 μg/kg/day BPA stop-dose); peaking at 2.5 μg BPA dose. No dorsal, ventral lobe effect. | Lateral lobe PIN severity increased after adult T + E at all BPA doses (neonatal 0.1 to 5000 μg). Dorsal and ventral lobe increased at 100 μg BPA. | CLARITY-BPA confirmed prior publications showing increased prostate carcinogenic susceptibility to elevated E2 in adulthood. | |
| Increased carcinoma multiplicity (4-fold) in dorsolateral prostate ducts at 1 year after adult T + E at 2.5 μg BPA (stop-dose). | Increased carcinoma incidence in lateral prostate at 1 year after adult T + E at neonatal 10 μg BPA dose. | CLARITY-BPA data confirm our prior studies that low-dose BPA exposure increases prostate cancer after secondary estrogen exposure. | |
| Increased prostate stem-like cells at 6 mo. for 2.5 μg BPA (continuous-dose); increased prostate progenitor cells at 25, 250 μg/kg/day BPA; altered lineage differentiation at 2.5, 25, 250 μg/kg/day BPA doses. | Human prostate stem-like and progenitor cell proliferation and gene expression shifts at 10 μM BPA exposure in vitro. | Consistent results between CLARITY-BPA and prior studies with human prostate stem-like and progenitor cells showing low-dose BPA increases cell numbers and reprograms gene expression. | |
| Urogenital sinus (male) | Size of the urethra altered by 2.5, 25, 250 μg/kg/day BPA. | Small urethra. | Same results in CLARITY-BPA as published previously for same endpoint examined. |
| Shape of the colliculus altered by 2.5, 25, 250 μg/kg/day BPA. | Enlarged dorsolateral prostate, colliculus and utricle. | ||
| Urothelium thickness reduced by 25, 250, 2500 μg/kg/day BPA. | Increase in androgen receptors in the urogenital sinus. | ||
| Enlarged bladder. | |||
| Hydronephrosis, obstructive voiding disorder. | |||
| Size of colliculus increased by 2.5, 25, 250 μg/kg/day BPA. | |||
| Ovary | Number of primary, preantral, and total healthy follicles decreased in 2.5 and 250 μg/kg/day BPA. | BPA exposure at 10 and 100 μg/mL inhibits antral follicle growth and increases atresia in vitro. | CLARITY-BPA data confirm prior studies indicating that BPA exposure interferes with folliculogenesis. |
| Serum estradiol levels decreased in 2500 and 25,000 μg/kg/day BPA. | BPA exposure at 10 and 100 μg/mL inhibits steroidogenesis, leading to low estradiol levels in vitro. | Consistent results between CLARITY-BPA and prior studies with mice and rats indicating that BPA exposure impairs steroidogenesis and causes low E2 levels. | |
| Neurobehavior –spatial learning | Escape tasks in Barnes maze, increased latency in 2500 μg/kg/day BPA females, and trend for increased latency in 2.5 μg/kg/day BPA females at PND 90; males exposed to 2.5 μg/kg/day BPA show trend for improved latency, but relevance of this finding is uncertain. | Male deer mice developmentally exposed to BPA through maternal diet (5 mg or 50 mg/kg feed weight) show reduced spatial navigational learning and memory. | CLARITY-BPA studies differ from our current findings that show males are more vulnerable to BPA-induced cognitive disruptions. |
| Exposure to 2500 μg/kg/day BPA disrupts patterns of sexually dimorphic gene expression/promoter. | Female deer mice exposed to BPA through the maternal diet (5 mg or 50 mg/kg feed weight) either show no affect or a trend for a masculinized response with improved latency. | Conflicting findings may be due to different rodent models (NCTR Sprague-Dawley rats vs. deer mice), route of exposure (oral gavage vs. dietary), dose and duration of BPA exposure, and other potential factors. | |
| Hippocampus of 2500/kg/day μg BPA female offspring have hypermethylated putative 5’ promoter regions of Bdnf. | |||
| Bdnf methylation weakly associated with Bdnf expression in hippocampi of female rats. | |||
| Neurobehavior –anxiety and juvenile anatomy | No systematic effects of BPA observed on any endpoint related to anxiety and exploration in juveniles or adults. | Expansive literature by us and others shows heightened anxiety in multiple species, including rats, mice, deer mice, and prairie voles. | In CLARITY-BPA, not all expected behavioral sex differences were observed in NCTR-Sprague Dawley rats, suggesting unique strain differences. |
| In juveniles, statistically significant effects of 2.5 and 25 μg/kg/day BPA identified on few endpoints in the interval open field analysis, but overall evidence for BPA-related effects minimal and inconsistent. | Changes in AVPV volume. | No effect of EE on behavior or AVPV volume in CLARITY-BPA raises some question about the sensitivity of this strain to the masculinizing influence of estrogen and/or efficacy of EE in the brain. | |
| Enlarged female AVPV at all BPA dose levels; male AVPV enlargement at 25 and 2500 μg/kg/day BPA doses. | Changes in AVPV neuron numbers, TH, and kisspeptin. | CLARITY-BPA results on AVPV and MePD volume are consistent with our prior work in rats showing BPA-related effects on AVPV volume and sexual differentiation and gene expression changes in the juvenile amygdala. | |
| Enlarged MePD (right side only) in males exposed to 2500 μg/kg/day BPA. | Disruption of gene expression in juvenile rat amygdala, including downregulation of Erβ, and sex‐specific disruption of Mc4r, Mc3r, and Tac2. | ||
| Disrupted ER expression in female juveniles of the same strain examined as part of the subchronic study that preceded CLARITY-BPA. | |||
| Neonatal neurodevelopment – PND 1 transcriptome | Sex and dose-specific effects on hypothalamic, hippocampal, and amygdalar transcriptome. | Disruption of hypothalamic PND 1 ER expression in the same strain following prenatal exposure. | Disruption of ER expression, particularly in the hypothalamus, is one of the most consistent findings across BPA literature. In every NCTR study we have worked on, including CLARITY-BPA, ER expression is disrupted at doses as low as 2.5 μg BPA. |
| Disruption of ER expression in hypothalamus, hippocampus, and amygdala. | Disruption of ERβ expression across postnatal rat brain. | We have also found evidence of disrupted oxytocin and vasopressin signaling in adult rats and prairie voles. | |
| Disruption of OT and AVP or its receptors in hippocampus, hypothalamus, and amygdala. | Interference with GABAergic and glutamatergic signaling has also been shown in several different capacities. | ||
| Disruption of genes and pathways related to GABA and glutamate signaling in the amygdala. | |||
| Heart | Decreased collagen in hearts at PND 90 and age 6 mo. | Altered rapid estrogen signaling in females that involves activation of ER. | Same results in CLARITY-BPA as published previously for same endpoint examined. |
| Myocardial degeneration in males and females at PND 21 and 90. | |||
| Female cardiomyopathy incidence and severity at PND 21 at BPA doses of 2.5, 250 and 25,000 μg/kg/day. | In vivo studies demonstrate that BPA exposure sex-specifically alters collagen content, modifies the extracellular matrix of hearts of both males and females, alters fatty acid and glycolytic metabolism, and increases sensitivity of the female heart to ischemic damage. | ||
| Increased sensitivity of heart to ischemic damage. | |||
| BPA significantly decreased heart weight and heart weight normalized to body weight in females exposed to 2.5 μg/kg/day BPA. | |||
| Thyroid | No effect on body weight. | Body weight of dams reduced in dose-dependent manner. | CLARITY-BPA is the only published study that does not report an effect of BPA on serum T4. |
| No effect on serum T4. | Serum T4 in pups increased on PND 15 but not on PND 8, or 35 (dosing stopped at weaning). | ||
| No effect on brain endpoints. | TSH not affected in pups. | ||
| PTU decreased serum T4 as expected. | RC3/neurogranin mRNA increased in dentate gyrus of PND 15 brain. | ||
| PTU did not affect brain endpoints known to be affected by thyroid hormone. | |||
| Mammary gland | Altered morphology of the mammary gland; non-monotonic dose-response curves to BPA with a breaking point between 25 and 250 μg/kg/day BPA doses. | Altered mammary gland morphology, non-monotonic dose response curves, intraductal hyperplasia and neoplasms, changes in methylome and transcriptome resulting from developmental BPA exposure, at doses as low as 25 ug/kg/day. Different effects of BPA and EE. | Morphological results expand our previous work demonstrating non-monotonic dose-responses to BPA exposure. In the Core study, significant increase of adenocarcinomas and adenomas in the lowest dose (2.5 μg) when exposure stopped at PND 21 is consistent with our early findings. |
| Although for some endpoints BPA and EE had similar results, for other endpoints the results were different and even opposite. | |||
| Data on methylome and transcriptome are highly suspect of contamination as a result of co-housing 53 of the 56 animals with those receiving the highest BPA dose. | |||
| Neoplastic results found in Core study, but this part of study had too few animals to measure incidence. |