Abstract
Dioxins are persistent organic pollutants interfering with endocrine systems and causing reproductive and developmental disorders. The objective of our project was to determine the impact of an in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on reproductive function of male and female offspring in the rat with a special emphasis on the immature period. We used a low dose of TCDD (unique exposure by oral gavage of 200 ng/kg at 15.5 days of gestation) in order to mirror a response to an environmental dose of TCDD not altering fertility of the progeny. We choose a global gene expression approach using Affymetrix microarray analysis, and testes of 5 days and ovaries of 14 days of age. Less than 1% of the expressed genes in gonads were altered following embryonic TCDD exposure; specifically, 113 genes in ovaries and 56 in testes with 7 genes common to both sex gonads. It included the repressor of the aryl hydrocarbon receptor (Ahrr), the chemokines Ccl5 and Cxcl4 previously shown to be regulated by dioxin in testis, Pgds2/Hpgds and 3 others uncharacterized. To validate and extend the microarray data we realized real-time PCR on gonads at various developmental periods of interest (from 3 to 25 days for ovaries, from 5 to the adult age for testes). Overall, our results evidenced that both sex gonads responded differently to TCDD exposure. For example, we observed induction of the canonic battery of TCDD-induced genes coding enzymes of the detoxifying machinery in ovaries aged of 3–14 days of age (except Cyp1a1 induced at 3–10 days) but not in testes of 5 days (except Ahrr). We also illustrated that inflammatory pathway is one pathway activated by TCDD in gonads. Finally, we identified several new genes targeted by TCDD including Fgf13 in testis and one gene, Ptgds2/Hpgds regulated in the two sex gonads.
Highlights
Dioxins, which refer to a family of structurally and chemically related polychlororinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) are lipophilic chemicals resistant to degradation and categorized as persistent organic pollutants, with 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) being the most toxic dioxin
We identified several new genes targeted by TCDD including Fgf13 in testis and one gene, Ptgds2/Hpgds regulated in the two sex gonads
Reproductive Parameters of the F1 Offspring A follow-up of the female offspring including body weight, fertility assessment and measurement of mRNA levels of some key genes involved in the endocrine function of the ovary during prepubertal period is provided (Supporting Information S1)
Summary
Dioxins, which refer to a family of structurally and chemically related polychlororinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) are lipophilic chemicals resistant to degradation and categorized as persistent organic pollutants, with 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD) being the most toxic dioxin. Dioxins are suspected of interfering with the endocrine systems of humans and wildlife [1,2,3] causing a broad spectrum of adverse effects including developmental and reproductive toxicity in the offspring of laboratory animals, and perhaps in humans. These disorders are of very high concern, because they occur at much lower doses than those causing wasting syndrome or carcinogenesis [4]. Dioxins tend to accumulate in the food chain, essentially fatty food including breast milk, and may cross the placental barrier These data emphasize that foetuses and neonates are vulnerable populations. It has been shown that TCDD exposure in utero is associated with malformations of external genitalia, reduced fertility, and disruption of estrus cycles and inhibition of ovulation [9,10]
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