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Toxicokinetics of the CYP11B1-activated adrenal toxicant 3-MeSO2-DDE in mother and offspring following oral administration to lactating minipigs
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
Department of Production Animal Clinical Sciences, Section of stationary clinic, Norwegian School of Veterinary Science.
Department of Production Animal Clinical Sciences, Section of stationary clinic, Norwegian School of Veterinary Science.
Department of Production Animal Clinical Sciences, Section of stationary clinic, Norwegian School of Veterinary Science.
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(English)Manuscript (Other academic)
Abstract [en]

3-Methylsulfonyl-4,4’-DDE (3-MeSO2-DDE) is a persistent and bioaccumulative metabolite of 4,4’-DDT, formed through biotransformation of 4,4’-DDE and characterized by a high and tissue-specific toxicity in the adrenal cortex in mouse fetuses, suckling pups and adult mice. 3-MeSO2-DDE also targets the human adrenal cortex kept in tissue-culture ex-vivo and human adrenocortical H295R cells in vitro. The present study was designed to examine the excretion of 3-MeSO2-DDE in milk and the maternal and neonatal toxicokinetics following a single oral dose to lactating minipigs. Milk, maternal fat, and plasma from five pigs and their suckling offspring were collected at regular intervals during four weeks. At autopsy on day 30 post partum, adrenals, liver and body fat were sampled from mothers and piglets. The levels of 3-MeSO2-DDE were measured by gas chromatography and the toxicokinetics in mothers and offspring were computed. The levels of 3-MeSO2-DDE in milk were considerably higher than in maternal and offspring plasma throughout the investigation. Based on both fresh weight and fat contents, the 3-MeSO2-DDE plasma levels in the piglets were about five times higher than in the mothers. A strong accumulation of 3-MeSO2-DDE was observed in fat tissue and a moderate accumulation in adrenals and liver of mothers and offspring. The retained tissue levels in the piglets were consistently higher than in the mothers. It is concluded that suckling offspring were more exposed than their mothers, which were given 3-MeSO2-DDE orally. The results suggest that human risk assessment of the adrenocorticolytic environmental pollutant 3-MeSO2-DDE should be focussed on breast-fed infants. Also in highly 4,4’-DDE- and 3-MeSO2-DDE-exposed marine mammals, the risks posed by 3-MeSO2-DDE are likely most pronounced during the postnatal period

Keyword [en]
Göttingen minipig, toxicokinetics, milk, lactation, adrenal cortex
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
URN: urn:nbn:se:su:diva-26966OAI: oai:DiVA.org:su-26966DiVA: diva2:212132
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
Open this publication in new window or tab >>Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DDT was extensively and globally used as a pesticide in agriculture and for malaria vector control from the 1940’s until the 1970’s. Due to its heavy use, DDT became ubiquitously distributed throughout the environment. DDT and several DDT metabolites are persistent organic pollutants. Two DDT metabolites, 3-MeSO2-DDE and o,p’-DDD have been proved to be tissue specific toxicants in the adrenal cortex. They are bioactivated to reactive intermediates which bind covalently to the adrenal cortex causing cell death. Due to its tissue specific toxicity o,p’-DDD has been used as a chemotherapy drug for adrenal cancer in humans. The efficacy and potency is however low and o,p’-DDD treatment is associated with serious side effects. 3-MeSO2-DDE has been suggested as a potential alternative therapeutic agent.

A key aim of this thesis has been to improve the understanding of the kinetics of the two adrenocorticolytic compounds o,p’-DDD, its two enantiomers and 3-MeSO2-DDE. To meet this objective chemical synthesis and enantioselective analysis were required. Furthermore, in vitro toxicity of o,p’-DDD enantiomers and diastereomers were performed.

An 11 step synthesis of 3-SH-DDE has been developed to promote both labelled and unlabelled synthesis of 3-alkylsulfonyl-DDE. Toxicokinetic studies showed that 3-MeSO2-DDE and o,p’-DDD were accumulated in tissues and retained in adipose tissue in minipigs. 3-MeSO2-DDE however had a twice as long biological t1/2 and a considerably lower Vd compared to o,p’-DDD. Suckling offspring were more exposed to 3-MeSO2-DDE than their mothers who were given 3-MeSO2-DDE orally. Interindividual differences in enantiomer kinetics in minipigs were observed suggesting polymorphism among the minipigs. Preparative isolation of the o,p’-DDD enantiomers is presented allowing determination of the absolute structures of the o,p’-DDD enantiomers by X-ray. The pure enantiomer of o,p’-DDD showed significant differences in toxicity in human adrenocortical cells.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Chemistry, Stockholm Univerisity , 2009. 55 p.
Keyword
o, p'-DDD, 3-Methylsulfonyl-DDE, adrenocorticolytic compounds, chiral
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-26952 (URN)978-91-7155-829-9 (ISBN)
Public defence
2009-05-29, Magnélisalen, Svante Arrhenius väg 12 A, Stockholm, 10:00 (Swedish)
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Supervisors
Available from: 2009-05-08 Created: 2009-04-21 Last updated: 2009-04-23Bibliographically approved

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