Maternal Exposure to Dioxin Imprints Sexual Immaturity of the Pups through Fixing the Status of the Reduced Expression of Hypothalamic Gonadotropin-Releasing Hormone

Abstract

Our previous studies have shown that treatment of pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 1 mg/kg) at gestational day (GD) 15 reduces the pituitary synthesis of luteinizing hormone (LH) during the late fetal and early postnatal period, leading to the imprinting of defects in sexual behaviors at adulthood. However, it remains unclear how the attenuation of pituitary LH is linked to sexual immaturity. To address this issue, we performed a DNA microarray analysis to identify the gene(s) responsible for dioxin-induced sexual immaturity on the pituitary and hypothalamus of male pups, born of TCDD-treated dams, at the age of postnatal day (PND) 70. Among the reduced genes, we focused on gonadotropin-releasing hormone (GnRH) in the hypothalamus because of published evidence that it has a role in sexual behaviors. An attenuation by TCDD of GnRH expression emerged at PND4, and no subsequent return to the control level was seen. A change in neither DNA methylation nor histone acetylation accounted for the reduced expression of GnRH. Intracerebroventricular infusion of GnRH to the TCDD-exposed pups after reaching maturity restored the impairment of sexual behaviors. Supplying equine chorionic gonadotropin, an LHmimicking hormone, to the TCDD-exposed fetuses at GD15 resulted in a recovery from the reduced expression of GnRH, as well as from the defects in sexual behavior. These results strongly suggest that maternal exposure to TCDD fixes the status of the lowered expression of GnRH in the offspring by reducing the LH-assisted steroidogenesis at the perinatal stage, and this mechanism imprints defects in sexual behaviors at adulthood.

Sperm quality and fertility in rats after prenatal exposure to low doses of TCDD: A three-generation study

“…TCDD, a congener of dioxin, is considered the most toxic environmental contaminant [38], is capable of inducing several adverse effects on human health [26,43,44], exerts estrogenic, antiestrogenic and anti-androgenic activities, depending on dose and time of exposure [45], and is able to perturb the normal development of the hypothalamus, leading to alterations in sexual differentiation [46]. It is known that this compound can be transferred to developing organisms through the placenta or by lactation [6], although we have not measured TCDD in milk.…”

Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

“…Recent studies in mammals (Wu et al , 2004; Okino et al , 2006; McClure et al , 2011; Singh et al , 2011; Manikkam et al , 2012a; Manikkam et al , 2012b; Takeda et al , 2012; Somm et al , 2013; Takeda et al , 2014) and zebrafish (Olsvik, et al, 2014) have demonstrated that exposure to TCDD alters DNA methylation patterns not only in the exposed generation, but also in subsequent generations. However, the mechanism of action by which toxicants affect DNA methylation is unknown.…”

Can resveratrol attenuate testicular damage in neonatal and adult rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin during gestation?

“…Humans are exposed to dioxins on a daily basis, and those living in more industrialised countries have an increased exposure (Schecter et al 2003). Exposure to dioxins, especially during pregnancy, had adverse effects in rats, as indicated by both behavioural (Takeda et al 2014) and reproductive parameters (Bjerke and Peterson 1994). 5 per group).…”