Hormesis: U-shaped dose responses and their centrality in toxicology

Calabrese, Edward J.; Baldwin, Linda A.

doi:10.1016/s0165-6147(00)01719-3

Cited by 372 publications

(217 citation statements)

References 38 publications

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“…One study, examining a relatively small toxicology database, concluded that NMDRCs were present in 12-24% of all dose response studies, and further proposed that this could be an underestimate due to biases against studies that do not report monotonic responses (Davis and Svendsgaard, 1994). Other studies report non-monotonic hormetic responses in more than 20% of toxicology studies (Calabrese and Baldwin, 2001a;Calabrese and Baldwin, 2001b;Calabrese and Baldwin, 2001c). Thus, our results are consistent with other quantitative assessments of NMDRCs.…”

Section: Discussionsupporting

confidence: 91%

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study

Vandenberg¹

2013

Dose-Response

303

156

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ᮀ Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not 'common enough' to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where 'safe' low doses are predicted from high dose exposures.

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Section: Discussionsupporting

confidence: 91%

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study

Vandenberg¹

2013

Dose-Response

303

156

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“…1A). Hormetic or biphasic responses of this type are characteristic of a broad range of physiological and behavioral responses and may represent an overcompensation in response to disruptions in homeostasis (Calabrese and Baldwin 2001). Post-hoc analysis revealed that the low-dose groups froze significantly more than either the vehicle or high-dose groups (Ps < 0.05, Student-Newman-Keuls).…”

mentioning

confidence: 96%

Exchange protein activated by cAMP enhances long-term memory formation independent of protein kinase A

Ma¹,

Abel²,

Hernandez³

2009

Learn. Mem.

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It is well established that cAMP signaling within neurons plays a major role in the formation of long-term memories—signaling thought to proceed through protein kinase A (PKA). However, here we show that exchange protein activated by cAMP (Epac) is able to enhance the formation of long-term memory in the hippocampus and appears to do so independent of PKA, thus demonstrating the importance of Epac-mediated signaling in memory consolidation.

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“…Of interest, some EACs display biphasic effects within large dose ranges (Kemppainen & Wilson 1996, vom Saal et al 1997, Maness et al 1998, Calabrese 2001a,b, Putz et al 2001a,b, Almstrup et al 2002, Terouanne et al 2003, Kohlerova & Skarda 2004. In parallel to this, the concept of hormesis has increasingly gained advocacy in recent years as a dose-response scheme for xenobiotics (Calabrese & Baldwin 2001a, Calabrese 2005. A hormetic doseresponse curve, either U-or inverted U-shaped, challenges the default linear model, which has been in practice for decades.…”

Section: Discussionmentioning

confidence: 99%

Non-monotonic dose–response relationship in steroid hormone receptor-mediated gene expression

Li¹,

Andersen²,

Heber³

et al. 2007

Journal of Molecular Endocrinology

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Steroid hormone receptors are the targets of many environmental endocrine active chemicals (EACs) and synthetic drugs used in hormone therapy. While most of these chemical compounds have a unidirectional and monotonic effect, certain EACs can display non-monotonic dose-response behaviors and some synthetic drugs are selective endocrine modulators. Mechanisms underlying these complex endocrine behaviors have not been fully understood. By formulating an ordinary differential equation-based computational model, we investigated in this study the steady-state doseresponse behavior of exogenous steroid ligands in an endogenous hormonal background under various parameter conditions. Our simulation revealed that non-monotonic dose-responses in gene expression can arise within the classical genomic framework of steroid signaling. Specifically, when the exogenous ligand is an agonist, a U-shaped dose-response appears as a result of the inherently nonlinear process of receptor homodimerization. This U-shaped dose-response curve can be further modulated by mixed-ligand heterodimers formed between endogenous ligandbound and exogenous ligand-bound receptor monomers. When the heterodimer is transcriptionally inactive or repressive, the magnitude of U-shape increases; conversely, when the heterodimer is transcriptionally active, the magnitude of U-shape decreases. Additionally, we found that an inverted U-shaped dose-response can arise when the heterodimer is a strong transcription activator regardless of whether the exogenous ligand is an agonist or antagonist. Our work provides a novel mechanism for non-monotonic, particularly U-shaped, dose-response behaviors observed with certain steroid mimics, and may help not only understand how selective steroid receptor modulators work but also improve risk assessment for EACs.

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Hormesis: U-shaped dose responses and their centrality in toxicology

Cited by 372 publications

References 38 publications

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study

Exchange protein activated by cAMP enhances long-term memory formation independent of protein kinase A

Non-monotonic dose–response relationship in steroid hormone receptor-mediated gene expression

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