Steroid metabolism in the brain: From bird watching to molecular biology, a personal journey

Balthazart, Jacques

doi:10.1016/j.yhbeh.2017.05.017

Cited by 21 publications

(8 citation statements)

References 155 publications

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“…This may explain why BPA is so often observed to be "estrogenic" in vivo, despite its limited binding affinity for ERs in vitro [135,136]. This is particularly significant given that the brain can synthesize its own estrogen and is thus not necessarily dependent on circulating levels [137,138]. Disruption of brain ER is one of the most consistently observed outcomes of developmental BPA exposure.…”

Section: Discussionmentioning

confidence: 99%

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Heindel

Belcher

Flaws

et al. 2020

Reproductive Toxicology

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Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY-BPA) was a comprehensive "industry-standard" Good Laboratory Practice (GLP)-compliant 2-year chronic exposure study of bisphenol A (BPA) toxicity that was supplemented by hypothesis-driven independent investigator-initiated studies. The investigator-initiated studies were focused on integrating disease-associated, molecular, and physiological endpoints previously found by academic scientists into an industry standard guideline-compliant toxicity study. Thus, the goal of this collaboration was to provide a more comprehensive dataset upon which to base safety standards and to determine whether industry-standard tests are as sensitive and predictive as molecular and disease-associated endpoints. The goal of this report is to integrate the findings from the investigator-initiated studies into a comprehensive overview of the observed impacts of BPA across the multiple organs and systems analyzed. For each organ system, we provide the rationale for the study, an overview of methodology, and summarize major findings. We then compare the results of the CLARITY-BPA studies across organ systems with the results of previous peer-reviewed studies from independent labs. Finally, we discuss potential influences that contributed to differences between studies. Developmental exposure to BPA can lead to adverse effects in multiple organs systems, including the brain, prostate gland, urinary tract, ovary, mammary gland, and heart. As published previously, many effects were at the lowest dose tested, 2.5μg/kg /day, and many of the responses were non-monotonic. Because the low dose of BPA affected endpoints in the same animals across organs evaluated in different labs, we conclude that these are biologically-and toxicologically-relevant.

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Section: Discussionmentioning

confidence: 99%

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Heindel

Belcher

Flaws

et al. 2020

Reproductive Toxicology

View full text Add to dashboard Cite

show abstract

“…This may explain why BPA is so often observed to be “oestrogenic” in vivo, despite its limited binding affinity for ERs in vitro . Region‐specific up‐regulation of ERs is also particularly significant given that it is now widely recognised that the brain can synthesise its own steroid hormones, including oestradiol, and thus is not necessarily dependent on circulating levels . Disruption of brain ER (both mRNA and protein levels) is one of the most consistently observed outcomes of developmental BPA exposure.…”

Section: Discussionmentioning

confidence: 99%

Achieving CLARITY on bisphenol A, brain and behaviour

Patisaul

2019

J Neuroendocrinology

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There is perhaps no endocrine disrupting chemical more controversial than bisphenol A (BPA). Comprising a high‐volume production chemical used in a variety of applications, BPA has been linked to a litany of adverse health‐related outcomes, including effects on brain sexual differentiation and behaviour. Risk assessors preferentially rely on classical guideline‐compliant toxicity studies over studies published by academic scientists, and have generally downplayed concerns about the potential risks that BPA poses to human health. It has been argued, however, that, because traditional toxicity studies rarely contain neural endpoints, and only a paucity of endocrine‐sensitive endpoints, they are incapable of fully evaluating harm. To address current controversies on the safety of BPA, the United States National Institute of Environmental Health Sciences, the National Toxicology Program (NTP), and the US Food and Drug Administration established the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY‐BPA). CLARITY‐BPA performed a classical regulatory‐style toxicology study (Core study) in conjunction with multiple behavioural, molecular and cellular studies conducted by academic laboratories (grantee studies) using a collaboratively devised experimental framework and the same animals and tissues. This review summarises the results from the grantee studies that focused on brain and behaviour. Evidence of altered neuroendocrine development, including age‐ and sex‐specific expression of oestrogen receptor (ER)α and ERβ, and the abrogation of brain and behavioural sexual dimorphisms, supports the conclusion that developmental BPA exposure, even at doses below what regulatory agencies regard as “safe” for humans, contribute to brain and behavioural change. The consistency and the reproducibility of the effects across CLARITY‐BPA and prior studies using the same animal strain and almost identical experimental conditions are compelling. Combined analysis of all of the data from the CLARITY‐BPA project is underway at the NTP and a final report expected in late 2019.

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“…Aromatase activity is modulated by steroid-related transcriptional changes but also more rapidly by phosphorylation cascades. Sexual activity of both male and female rodents may also affect brain aromatase activity, probably through glutamatergic signaling (Balthazart 2017; de Bournonville et al 2017; Antaramian et al 2015). Recent evidence suggests a role for brain aromatase in the development of serotoninergic pathways in lower vertebrates (Ulhaq and Kishida 2018).…”

Section: Introductionmentioning

confidence: 99%

Chronic Antipsychotic Treatment Modulates Aromatase (CYP19A1) Expression in the Male Rat Brain

et al. 2019

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Antipsychotic drugs, known as the antagonists of dopaminergic receptors, may also affect a large spectrum of other molecular signaling pathways in the brain. Despite the numerous ongoing studies on neurosteroid action and regulation, there are no reports regarding the influence of extended treatment with typical and atypical neuroleptics on brain aromatase (CYP19A1) expression. In the present study, we assessed for the first time aromatase mRNA and protein levels in the brain of rats chronically (28 days) treated with olanzapine, clozapine, and haloperidol using quantitative real-time PCR, end-point RT-PCR, and Western blotting. Both clozapine and haloperidol, but not olanzapine treatment, led to an increase of aromatase mRNA expression in the rat brain. On the other hand, aromatase protein level remained unchanged after drug administration. These results cast a new light on the pharmacology of examined antipsychotics and contribute to a better understanding of the mechanisms responsible for their action. The present report also underlines the complex nature of potential interactions between neuroleptic pharmacological effects and physiology of brain neurosteroid pathways.

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Steroid metabolism in the brain: From bird watching to molecular biology, a personal journey

Cited by 21 publications

References 155 publications

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Data integration, analysis, and interpretation of eight academic CLARITY-BPA studies

Achieving CLARITY on bisphenol A, brain and behaviour

Chronic Antipsychotic Treatment Modulates Aromatase (CYP19A1) Expression in the Male Rat Brain

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