Dioxin Resistance Alleles and Developmental Stage at Exposure as Determinants of Sensitivity to Dioxin-Induced Short-Term Toxicity and Male Reproductive Effects
Year: 2004
Type: article
Abstract: The term "dioxins" generally means a heterogenous mixture of chlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs).Dioxins are widespread and persistent environmental contaminants, and due to their lipophilicity and slow metabolism they accumulate in food chain.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic dioxin congener, and is referred to as "the most toxic man-made compound".Humans are exposed to dioxins primarily via the food.In Finland, 80% of human exposure comes from fish, Baltic fish being the most crucial source.Therefore, the European Commission is planning actions to limit the consumption of Baltic fish, especially herring and salmon.TCDD causes a wide variety of biochemical and toxic effects that are mostly mediated through the aryl hydrocarbon receptor (AHR).These effects have been reported in multiple species and at different stages of development.Defects in the developing male reproductive system and teeth are among the most sensitive endpoints of TCDD toxicity in laboratory animals.This study outlines two important questions in dioxin risk assessment:(1) What is the role of genetic factors in sensitivity to dioxins?This issue was examined using two different animal models: a mouse model with Ahr null mutation and a rat model based on exceptional resistance to TCDD acute lethality.The TCDD resistance of these rats is due to a mutated Ahr allele (Ahr hw ) and an unknown allele B hw .Although the resistance alleles increase the resistance to hexachlorodibenzo-p-dioxin (HxCDD)induced acute lethality remarkably less than to TCDD and results in exceptional relative sensitivity to HxCDD, the study showed that the rats with Ahr hw and/or B hw resistance alleles are not exceptionally sensitive to HxCDD-induced non-lethal short-term effects.An efficacy (magnitude of effect) ratio of 0.5 between resistant and sensitive rats was found to categorize the dioxin short-term toxicity into different type I and type II endpoints.The resistance alleles do not modify type I endpoints (CYP1A1 induction, thymic atrophy and tooth defects), while especially the Ahr hw reduce the efficacy of type II endpoints (decreased body weight and liver toxicity).Although most if not all effects of TCDD on the developing prostate in mice were shown to be AHR mediated, the mutated Ahr hw in rats was still able to normally mediate the TCDD-induced defects in male reproductive organ development after adult and perinatal TCDD exposure.However, the extent of the decrease in sperm numbers after perinatal TCDD exposure was reduced by the resistance alleles.(2) How is dioxin sensitivity altered at different developmental stages?Toxic effects of TCDD on male reproductive system were observed in fetuses exposed to at least 100-times lower doses compared to those that alter male reproductive system after adult exposure.The critical time window for TCDD defects in developing prostate was found to differ among different prostate lobes.The growth of ventral and anterior prostate was most affected during fetal period, while that of dorsolateral prostate required both fetal and postnatal exposure for maximal effect.The development of resistance to acute lethality differed between rats having either one of the resistance alleles.Rats with Ahr hw were resistant to TCDD when assessed a few days after birth, while rats with allele B hw did not attain their resistance until four to six weeks after birth.This reflects basic differences in pathways mediating resistance linked to these alleles.Simanainen, Ulla.Geneettiset herkkyystekijät ja kehitysvaihe dioksiinien lyhytaikaistoksisuutta ja lisääntymistoksisuutta määräävinä tekijöinä.
Author: Ulla Simanainen
Language: English
Subfield: Health, Toxicology and Mutagenesis
Field: Environmental Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W1424485430