Developmental Exposure to Low-Dose PBDE-99: Effects on Male Fertility and Neurobehavior in Rat Offspring

Abstract

In utero exposure to a single low dose of 2,2′,4,4′,5-pentabromodiphenyl ether (PBDE-99) disrupts neurobehavioral development and causes permanent effects on the rat male reproductive system apparent in adulthood. PBDEs, a class of flame retardants, are widely used in every sector of modern life to prevent fire. They are persistent in the environment, and increasing levels of PBDEs have been found in biota and human breast milk. In the present study we assessed the effects of developmental exposure to one of the most persistent PBDE congeners (PBDE-99) on juvenile basal motor activity levels and adult male reproductive health. Wistar rat dams were treated by gavage on gestation day 6 with a single low dose of 60 or 300 μg PBDE-99/kg body weight (bw). In offspring, basal locomotor activity was evaluated on postnatal days 36 and 71, and reproductive performance was assessed in males at adulthood. The exposure to low-dose PBDE-99 during development caused hyperactivity in the offspring at both time points and permanently impaired spermatogenesis by the means of reduced sperm and spermatid counts. The doses used in this study (60 and 300 μg/kg bw) are relevant to human exposure levels, being approximately 6 and 29 times, respectively, higher than the highest level reported in human breast adipose tissue. This is the lowest dose of PBDE reported to date to have an in vivo toxic effect in rodents and supports the premise that low-dose studies should be encouraged for hazard identification of persistent environmental pollutants.

Assessing reproductive and endocrine parameters in male largescale suckers (Catostomus macrocheilus) along a contaminant gradient in the lower Columbia River, USA

“…Reductions in the percentages of normal sperm morphology have been related to high sperm chromatin fragmentation and lower motility (Spano et al, 1999). Consistent with this study with LSS showing no correlation between any BDE congeners and abnormal sperm morphologies, BDE-99 and BDE-209 administered to rodents did not result in abnormal morphologies (Kuriyama et al, 2005;Tseng et al, 2006).…”

“…In addition to affecting individuals at any life stage, many environmental EDCs can modify the germ line, resulting in transgenerational impacts to male fertility, as seen with vinclozin, methoxychlor (Anway et al 2005), BDE-99 (Kuriyama et al, 2005), and dioxin (Theobald and Peterson, 1997). Reproductive dysfunction in male fish due to EDC can reduce sperm numbers (Haubruge et al, 2000;Patiño et al, 2003), sperm motility (Jenkins et al, 2009;Lahnsteiner et al, 2006), and fertility (Lahnsteiner et al, 2006).…”

Developmental neurotoxicity of polybrominated diphenyl ether (PBDE) flame retardants

“…Alterations in the levels of circulating sex hormones (estradiol and testosterone) at weaning and in adulthood were also found in this study. In rats treated with BDE-99 under the same experimental protocol, Lichtensteiger et al (2004) also reported a decrease in sexual behavior in females, while Kuriyama et al (2005) did not find any alteration in sexual behavior in male rats prenatally exposed to a single low dose of BDE-99. In summary, available behavioral studies indicate that all PBDEs tested in rodents under different exposure protocols cause alterations in neurobehavioral development.…”

“…These values are not much dissimilar from the estimated exposure of infants to PBDEs (see Table 4). If one considers also the study by Kuriyama et al (2005) with BDE-99, in which the dose of 0.06 mg/kg was the LOEL (low-observed-effect-level) for hyperactivity, applying all safety factors (10x10x10x3) provides a RfD of 20 ng/kg/day. By considering interspecies toxicokinetic differences, based on differences in half-lifes (Geyer et al 2004;McDonald, 2005), which amount to about 50 fold, the safety factor for interspecies extrapolation could be 50 instead of 10.…”

Chronic exposure to environmental levels of tribromophenol impairs zebrafish reproduction

“…For example, oral exposure to the PBDE congener 2,2′,4,4′-tetrabromodiphenyl ether (PBDE-47) impaired reproductive activity in fathead minnow (Muirhead et al 2006). Exposure to low doses of 2,2′,4,4′,5-pentabromodiphenyl ether (PBDE-99) during critical periods of development permanently impairs spermatogenesis in adult rat offspring (Kuriyama et al, 2005) and PBDE-99 have also been shown to interfere with sexual development and sexually dimorphic behaviors, both of which are mediated by hormones produced in endocrine glands (Lilienthal et al, 2006). In fish, estradiol produced by the developing follicle stimulates the liver to produce the yolk protein vitellogenin (VTG, which is essential for vitellogenesis) and induces oocyte maturation and yolk biosynthesis; the yolk is sequestered and processed by the developing oocyte to provide nutrients for the offspring .…”