Unexpected gender difference in sensitivity to the acute toxicity of dioxin in mice

Pohjanvirta, Raimo; Miettinen, Hanna; Sankari, Satu; Hegde, Nagabhooshan; Lindén, Jere

doi:10.1016/j.taap.2012.04.032

Cited by 40 publications

(45 citation statements)

References 54 publications

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“…The transient doubling of ALAT and progressive increase of ASAT (reaching about four-fold values vs. controls on day 10) in TCDD-dosed L-E rats attest to a modest injury to hepatocytes, and differs markedly from our previous findings in C57BL/6Kuo male mice [9]. In those animals, a TCDD-dose of 500 μg/kg (roughly biologically equivalent to the one used in the current study) induced abundant random focal liver necrosis on day 6, accompanied by an over 30-fold increase in plasma ALAT but only a three-fold increase in ASAT.…”

Section: Resultscontrasting

confidence: 88%

“…In vivo , AHR protein was found to diminish initially but then show a tendency towards recovery, the speed and extent of which depended on rat strain and TCDD dose [116,117]. In mouse liver, the depression persisted for at least 6 days [9]. In the present study, AHR protein was rapidly and persistently lowered by TCDD in both rat strains, while AHR mRNA expression was fostered in L-E rats alone.…”

Section: Resultsmentioning

confidence: 52%

“…The principal features of acute TCDD toxicity, besides inter- and intra-species differences in susceptibility, are delayed lethality and drastic and persistent changes in body weight and feed intake [8,9]. Even high acute dioxin doses do not kill animals immediately, but death occurs in one to several weeks, and in many species (e.g., rats, mice, hamsters and guinea pigs), after substantially reduced feed intake and prominent weight loss [10,11,12,13], called the wasting syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain

Lindén

Lensu

Pohjanvirta

2014

IJMS

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One of the hallmarks of the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a drastically reduced feed intake by an unknown mechanism. To further elucidate this wasting syndrome, we followed the effects of a single large dose (100 μg/kg) of TCDD on the serum levels of several energy balance-influencing hormones, clinical chemistry variables, and hepatic aryl hydrocarbon receptor (AHR) expression in two rat strains that differ widely in their TCDD sensitivities, for up to 10 days. TCDD affected most of the analytes in sensitive Long-Evans rats, while there were few alterations in the resistant Han/Wistar strain. However, analyses of feed-restricted unexposed Long-Evans rats indicated several of the perturbations to be secondary to energy deficiency. Notable increases in ghrelin and glucagon occurred in TCDD-treated Long-Evans rats alone, which links these hormones to the wasting syndrome. The newly found energy balance regulators, insulin-like growth factor 1 and fibroblast growth factor 21 (FGF-21), appeared to function in concert in body weight loss-induced metabolic state, and FGF-21 was putatively linked to increased lipolysis induced by TCDD. Finally, we demonstrate a reverse set of changes in the AHR protein and mRNA response to TCDD and feed restriction, suggesting that AHR might function also as a physiological regulator, possibly involved in the maintenance of energy balance.

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Section: Resultscontrasting

confidence: 88%

Section: Resultsmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain

Lindén

Lensu

Pohjanvirta

2014

IJMS

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“…The gender and species reported in the ChemIDplus database are unknown. Studies on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to mice indicated that female mice are more resistant and the magnitude of the divergence between male and female mice can amount to over 10-fold (Pohjanvirta et al, 2012). Different LD 50 values have been observed between mouse strains (Aune et al, 2008).…”

Section: Effect Of Experimental Uncertainty Gender and Speciesmentioning

confidence: 99%

“…Analysis on the standard deviation of the toxicity data selected from published references showed the repeatability of acute toxicity measurements is good for most of the compounds but very low for some compounds (Hoffmann et al, 2010). Furthermore, the mouse toxicity is gender and species dependent (Aune et al, 2008;Pohjanvirta et al, 2012;Singh et al, 2014). This information on the gender and species is very valuable and should be reported in the data sets of QSARs.…”

Section: Introductionmentioning

confidence: 99%

Relationship between lethal toxicity in oral administration and injection to mice: Effect of exposure routes

Wang

Ning

Tai

et al. 2015

Regulatory Toxicology and Pharmacology

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Aryl hydrocarbon receptor‐based bioassays for dioxin detection: Thinking outside the box

Otarola

Castillo

Marcellini

2017

J of Applied Toxicology

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Despite intensive media coverage and international regulations, man-made persistent organic pollutants such as dioxins represent a serious environmental and health threat. Their detection by sophisticated chromatography technologies is highly complex, impeding the constant monitoring of food or environmental samples. This limitation has fostered the development of generations of bioassays exploiting the molecular function of the aryl hydrocarbon receptor (AhR), which binds toxic compounds and directly activates the transcription of target genes. Here, we review the rich panel of available AhR-dependent bioassays and propose a novel classification based on the source of AhR, which can either be endogenously produced by cell types or tissues naturally responsive to dioxins, or exogenously introduced into a wide range of cellular contexts. In both cases, in vitro and in vivo strategies have been engineered to monitor the formation of molecular complexes, and the activation of direct downstream targets or reporter genes. We evaluate and compare bioassays based on exogenous and endogenous AhR proteins and discuss their specific challenges, strengths and opportunities for futures applications. Undoubtedly, the dynamic field of AhR-dependent bioassays will keep providing new and original strategies to help protect human health and ecosystems from persistent organic pollutants.

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Unexpected gender difference in sensitivity to the acute toxicity of dioxin in mice

Cited by 40 publications

References 54 publications

Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain

Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on Hormones of Energy Balance in a TCDD-Sensitive and a TCDD-Resistant Rat Strain

Relationship between lethal toxicity in oral administration and injection to mice: Effect of exposure routes

Aryl hydrocarbon receptor‐based bioassays for dioxin detection: Thinking outside the box

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