Fetal and neonatal dioxin exposure causes sex-specific metabolic alterations in mice.

Publisher: Oxford University Press Country of Publication: United States NLM ID: 9805461 Publication Model: Print Cited Medium: Internet ISSN: 1096-0929 (Electronic) Linking ISSN: 10960929 NLM ISO Abbreviation: Toxicol Sci Subsets: MEDLINE

Publication: 1999- : Cary, NC : Oxford University Press
Original Publication: Orlando, FL : Academic Press, c1998-

Dioxins* ; Prenatal Exposure Delayed Effects*/chemically induced ; Polychlorinated Dibenzodioxins*/toxicity; Pregnancy ; Male ; Humans ; Mice ; Animals ; Female ; Reproduction ; Glucose/pharmacology

Epidemiological studies report associations between early-life exposure to persistent organic pollutants (POPs) and impaired metabolic homeostasis in adulthood. We investigated the impact of early-life exposure to low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or 'dioxin') on the establishment of β-cell area during the perinatal period, as well as β-cell health and glucose homeostasis later in life. Adult female mice were injected with either corn oil (CO; vehicle control) or TCDD (20 ng/kg/day) 2×/week throughout mating, pregnancy, and lactation; offspring were thus indirectly exposed to maternal TCDD in utero and during lactation, with pollutant exposure ending at weaning. All offspring were maintained on chow diet from weaning until 12-17 weeks of age, after which a subset of CO- and TCDD-exposed offspring were transferred to a 45% high fat diet (HFD) as a metabolic stressor for an additional 10 weeks. TCDD significantly upregulated cytochrome P450 1a1 (Cyp1a1) gene expression in offspring pancreas at birth and weaning, indicating that maternal TCDD directly reaches the developing pancreas. TCDD-exposed pups were transiently hypoglycemic at birth and females were born with reduced % β-cell area, which persisted into adulthood. Early-life TCDD exposure had no persistent long-term effects on glucose homeostasis in chow-fed offspring, but when transferred to HFD, TCDD-exposed female offspring had a delayed onset of HFD-induced hyperglycemia, more pronounced HFD-induced hyperinsulinemia, and increase % PCNA+ β-cells compared with CO-exposed female offspring. This study demonstrates that early-life exposure of mice to TCDD has modest effects on metabolic health in chow-fed offspring but alters metabolic adaptability to HFD feeding in females.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology.)

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PJT-2018-159590 Canada CIHR

Keywords: diabetes; dioxin; early-life pollutant exposure; hypoglycemia; metabolic adaptability; β-cell mass

0 (Dioxins)
0 (Polychlorinated Dibenzodioxins)
IY9XDZ35W2 (Glucose)

Date Created: 20230428 Date Completed: 20230630 Latest Revision: 20230702

20250114

PMC10306400

10.1093/toxsci/kfad042

37115651