Early‐life exposure to Tris(1,3‐dichloroisopropyl) phosphate induces dose‐dependent suppression of sexual behavior in male rats

Exposure to endocrine‐disrupting chemicals may adversely affect animals, particularly during development. Tris(1,3‐dichloroisopropyl) phosphate (TDCIPP) is an organophosphate with anti‐androgen function in vitro that is present in indoor dust at relatively high concentrations. In male rats, androgens are necessary for the development of reproductive organs, as well as the endocrine and central nervous systems. However, we currently do not know the exact effects of TDCIPP exposure through suckling on subsequent reproductive behavior in males. Here, we show that TDCIPP exposure (25–250 mg kg^–1 via oral administration over 28 consecutive days post‐birth) suppressed male sexual behavior and reduced testes size. These changes were dose‐dependent and appeared first in adults rather than in juveniles. These results demonstrate that TDCIPP exposure led to normal body growth and appearance in juveniles, but disrupted the endocrine system and physiology in adults. Therefore, assays should be performed using adult animals to ensure accuracy, and to confirm the influence of chemical substances given during early mammalian life.     

Comparison of tris(2-ethylhexyl) phosphate and di(2-ethylhexyl) phosphoric acid toxicities in a rat 28-day oral exposure study

Tris(2-ethylhexyl) phosphate (TEHP, CAS no. 78-42-2) is a plasticizer and a flame retardant, while di(2-ethylhexyl) phosphoric acid (DEHPA, CAS no. 298-07-7) is an oil additive and extraction solvent. Publicly-available information on repeated exposure to these two related organophosphate compounds is fragmentary. Hence, adult male and female Fischer rats were exposed to TEHP (300, 1000 and 3000 mg/kg body weight [BW]/day) or DEHPA (20, 60 and 180 mg/kg BW/day) by gavage for 28 consecutive days, to assess and compare their toxicities. Although significantly impaired BW gains and evidence of TEHP enzymatic hydrolysis to DEHPA were observed only in males, exposures to the highest TEHP and DEHPA doses often resulted in similar alterations of hematology, serum clinical chemistry and liver enzymatic activities in both males and females. The squamous epithelial hyperplasia and hyperkeratosis observed in the non-glandular forestomach of rats exposed to the middle and high DEHPA doses were most likely caused by the slightly corrosive nature of this chemical. Although tubular degeneration and spermatid retention were observed only in the testes of males exposed to the highest TEHP dose, numerous periodic acid-Schiff stained crystalline inclusions were observed in testis interstitial cells at all TEHP dose levels. No-observed-adverse-effect levels for TEHP and DEHPA are proposed, but the lower serum pituitary hormone levels resulting from TEHP and DEHPA exposures and the perturbations of testicular histology observed in TEHP-treated males deserve further investigation. Improved characterization of the toxicity of flame retardants will contribute to better informed substitution choices for legacy flame retardants phased-out over health concerns.     

Toxicological effects of Tris (1,3-dichloro-2-propyl) phosphate exposure in adult male rats differ depending on the history of exposure in the neonatal period

There is increasing concern about multiple high concentration exposure to toxins in disaster and emergency situations. However, conventional toxicology testing methods may not adequately address these situations. Thus, we assessed whether the toxic effects of exposure in the adulthood differ depending on the presence or absence of neonatal exposure to Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) in male rats to investigate the effects of exposure history of chemicals. In the neonatal stage [postnatal days (PNDs) 1–7], animals were treated with either sesame oil (5 ml/kg/day) as a control or TDCIPP (250 mg/kg/day) dissolved in sesame oil. In adulthood (PND 101–107), animals were treated with either sesame oil (5 ml/kg/day) or TDCIPP (650 mg/kg/day). One day after the final administration, dissection was performed, and body and organ weight, hematology, blood biochemistry, and histopathology were examined. The results demonstrated that the toxic effects of TDCIPP exposure in adulthood on adrenal gland size, serum iron content, and unsaturated iron binding capacity were enhanced by TDCIPP exposure in the neonatal stage. From these findings, it was indicated that the toxic effects of TDCIPP exposure in the adult stage are affected by pediatric exposure. These results suggest that the toxic effects of high-dose and long-term unsteady exposure to chemicals in large-scale disasters may change based on the exposure history of chemicals.     

Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-Dawley rats following subchronic (90 days) inhalation exposure

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese (Mn) compound added to unleaded gasoline in Canada. The primary combustion products of MMT are Mn phosphate, Mn sulfate, and a Mn phosphate/Mn sulfate mixture. Concerns have been raised that the combustion products of MMT containing Mn could be neurotoxic, even at low levels of exposure. The objective of this study is to investigate exposure-response relationships for bioaccumulation and locomotor effects following subchronic inhalation exposure to a mixture of manganese phosphates/sulfate mixture. A control group and three groups of 30 male Sprague-Dawley rats were exposed in inhalation chambers for a period of 13 weeks, 5 days per week, 6 h a day. Exposure concentrations were 3000, 300, and 30 microg/m(3). At the end of the exposure period, locomotor activity and resting time tests were conducted for 36 h using a computerized autotrack system. Rats were then euthanized by exsanguination and Mn concentrations in different tissues (liver, lung, testis, and kidney) and blood and brain (caudate putamen, globus pallidus, olfactory bulb, frontal cortex, and cerebellum) were determined by neutron activation analysis. Increased manganese concentrations were observed in blood, kidney, lung, testis, and in all brain sections in the highest exposure group. Mn in the lung and in the olfactory bulb were dose dependent. Our data indicate that the olfactory bulb accumulated more Mn than other brain regions following inhalation exposure. Locomotor activity was increased at 3000 microg/m(3), but no difference was observed in resting time among the exposed groups. At the end of the experiment, rats exposed to 300 and 3000 microg/m(3) exhibited significantly decreased body weight in comparison with the control group. Biochemical profiles also revealed some significant differences in certain parameters, specifically alkaline phospatase, urea, and chlorate.     

The induction of mounting behavior in female rats by p-chlorophenylalanine.

The effect of p-chlorophenylalanine (pCPA) and testosterone propionate (TP) on mounting behavior of ovariectomized female rats towards receptive and non-receptive stimulus females was studied. Both pCPA and TP facilitated mounting and the effect was intensified when these compounds were administered together. pCPA increased mounting behavior in the non-receptive stimulus condition. The results are interpreted as further evidence that pCPA affects sexual behavior in two ways: at first by a direct influence on the neutral substrate underlying masculine sexual behavior, and secondly by changing information processing of the sensory input from the partner.     

A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats.

A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabromocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at the lower 95% one-sided confidence bound (BMDL) at predefined critical effect sizes (CESs) of 10-20%. The most remarkable findings were dose-related effects on the thyroid hormone axis, that is, decreased total thyroxin (TT4, BMDL 55.5 mkd at CES--10%), increased pituitary weight (29 mkd at 10%) and increased immunostaining of TSH in the pituitary, increased thyroid weight (1.6 mkd at 10%), and thyroid follicle cell activation. These effects were restricted to females. Female rats also showed increased absolute liver weights (22.9 mkd at 20%) and induction of T4-glucuronyl transferase (4.1 mkd at 10%), suggesting that aberrant metabolization of T4 triggers feedback activation of the thyroid hormone system. These effects were accompanied by possibly secondary effects, including increased cholesterol (7.4 mkd at 10%), increased tibial bone mineral density (> 49 mkd at 10%), both in females, and decreased splenocyte counts (0.3-6.3 mkd at 20%; only evaluated in males). Overall, female rats appeared to be more sensitive to HBCD than male rats, and an overall BMDL is proposed at 1.6 mkd, based on a 10% increase of the thyroid weight, which was the most sensitive parameter in the sequence of events.     

Subacute effects of hexabromocyclododecane (HBCD) on hepatic gene expression profiles in rats

Hexabromoyclododecane (HBCD), used as flame retardant (FR) mainly in textile industry and in polystyrene foam manufacture, has been identified as a contaminant at levels comparable to other brominated FRs (BFRs). HBCD levels in biota are increasing slowly and seem to reflect the local market demand. The toxicological database of HBCD is too limited to perform at present a solid risk assessment, combining data from exposure and effect studies. In order to fill in some gaps, a 28-day HBCD repeated dose study (OECD407) was done in Wistar rats. In the present work liver tissues from these animals were used for gene expression profile analysis. Results show clear gender specificity with females having a higher number of regulated genes and therefore being more sensitive to HBCD than males. Several specific pathways were found to be affected by HBCD exposure, like PPAR-mediated regulation of lipid metabolism, triacylglycerol metabolism, cholesterol biosynthesis, and phase I and II pathways. These results were corroborated with quantitative RT-PCR analysis. Cholesterol biosynthesis and lipid metabolism were especially down-regulated in females. Genes involved in phase I and II metabolism were up-regulated predominantly in males, which could explain the observed lower HBCD hepatic disposition in male rats in this 28-day study. These sex-specific differences in gene expression profiles could also underlie sex-specific differences in toxicity (e.g. decreased thyroid hormone or increased serum cholesterol levels). To our knowledge, this is the fist study that describes the changes in rat hepatic gene profiles caused by this commonly used flame retardant.     

Hypoactive sexual desire disorder (HSDD) is not “female erectile dysfunction (ED)”: challenges with the characterization of HSDD in women based on a systematic literature review

Abstract

Objective: Hypoactive sexual desire disorder (HSDD) in women has been viewed inaccurately by some in the medical and payer community as analogous to erectile dysfunction (ED) in men. This literature review aims to highlight the distinctions between HSDD and ED.

Methods: Two systematic literature searches were conducted on the epidemiology, symptomatology and biopsychosocial outcomes of HSDD and ED. Studies published since 2007 were considered for HSDD; studies published since 2012 were considered for ED.

Results: HSDD in women is primarily a central nervous system condition related to neuroendocrine factors, whereby neural pathways that regulate sexual excitation and/or inhibition appear to be involved. A combination of organic and psychogenic factors often contributes to ED. HSDD and ED are associated with similar psychological and interpersonal consequences, but affect different phases of the sexual response model (desire versus arousal) and have different pathophysiologies, therefore requiring different treatment and outcome paradigms. ED is measured by objective, physiological responses (erection and sexual function), but quantitative assessments for HSDD are more difficult because loss of desire with associated distress has to be assessed. Outcome measures used to assess ED, such as the number of satisfying sexual events, are far less informative as an endpoint for randomized clinical trials of treatments for HSDD.

Conclusions: HSDD and ED are distinct conditions affecting different phases of the sexual response model, and thus require clear and unique clinical characterization and adequate communication between the health care professional and patient for appropriate diagnosis, management and treatment.     

Effects of prenatal exposure to morphine on the development of sexual behavior in rats

Females exposed to morphine sulfate in utero (5-10 mg/kg twice a day on days 11-18 of gestation) displayed precocious vaginal opening and had increased body weight from the 8th week after weaning. In addition, there was a substantial inhibition in adult feminine sexual behavior. Male rats that received either morphine or saline prenatally did not show any body weight differences, and most of the measures of masculine sexual behavior did not differ between the two groups. However, the male rats exposed to morphine had a significantly shorter post-ejaculatory intromission latency than the saline controls. Examination of cytosol estrogen receptor levels in the hypothalamus-preoptic area (HPOA) of both saline and morphine sulfate-treated female rats revealed essentially identical patterns of depletion and replenishment. Additionally, estrogen treatment was equally effective at inducing HPOA progestin receptor synthesis in both groups. These results show that prenatal morphine treatment at the times and dose level administered disrupts the development of reproductive function in females but has only minor effects on male reproductive function.     

A 28-day oral dose toxicity study in Wistar rats enhanced to detect endocrine effects of decabromodiphenyl ether (decaBDE)

Decabromodiphenyl ether (decaBDE) is a widely used brominated flame retardant, considered to be of low toxicity. However, previous toxicity studies applied exposure methods with low bioavailability of this compound, and the actual hazard of decaBDE for humans, which are environmentally exposed to decaBDE, may thus be underestimated in current risk assessments. The present 28 days oral toxicity study in Wistar rats was designed to facilitate detection of endocrine and immune modulating effects of decaBDE using an exposure protocol with improved bioavailability. A technical preparation of high purity decaBDE was thus tested by daily exposure through gavage with an emulsion of soy phospholipon/lutrol as a carrier. Most sensitive effect in males were increased weight of seminal vesicle/coagulation gland with BMDL of 0.2mg/kg bw/day and increased expression of hepatic CYP1A and CYP2B (BMDLs 0.5-0.7 mg/kg bw/day). In females the most sensitive effect was decreased activity of P450c17 (CYP17), which is a key enzyme in the androgen synthesis pathway, in adrenals (BMDL 0.18 mg/kg bw/day). These results suggest that decaBDE may represent an as yet unreported hazard for reproductive health.     

Bioaccumulation and locomotor effects of manganese sulfate in Sprague-Dawley rats following subchronic (90 days) inhalation exposure

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic compound that was introduced as an anti-knock additive to replace lead in unleaded fuel. The combustion of MMT results in the emission of fine Mn particulates mainly in the form of manganese sulfate and manganese phosphate. The objective of this study is to determine the effects of subchronic exposure to Mn sulfate in different tissues, on locomotor activity, on neuropathology, and on blood serum biochemical parameters. A control group and three groups of 30 male Sprague-Dawley rats were exposed 6-h/day, 5 days/week for 13 consecutive weeks at 30, 300, or 3,000 microg/m(3) Mn sulfate. Locomotor activity was measured during 36 h using an Auto-Track System. Blood and the following tissues were collected and analyzed for manganese content by neutron activation analysis: olfactory bulb, globus pallidus, caudate/putamen, cerebellum, frontal cortex, liver, lung, testis, and kidney. Neuronal cell counts were obtained for the caudate/putamen and the globus pallidus and clinical biochemistry was assessed. Manganese concentrations were increased in blood, kidney, lung, and testis and in all brain regions in the 3,000 microg/m(3) exposure group. Significant differences were also noted in the 300 microg/m(3) exposure group. Neuronal cell counts for the globus pallidus were significantly different between the two highest exposed groups and the controls. Locomotor activity for all exposure concentrations and resting time for the middle and highest concentrations for the two night resting periods were significantly increased. Total ambulatory count was decreased significantly for all exposure concentrations. Biochemical profiles also presented significant differences. No body weight loss was observed between all groups. These results suggest that neurotoxicity could occur at low exposure levels of Mn sulfate, one of the main combustion products of MMT.     

Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study.

Testosterone plays a major role in male sexual development. Exposure of females to testosterone in utero can induce masculine characteristics such as anovulation, increased anogenital distance (AGD), absence of nipples, retention of male-like tissues, and agenesis of the lower vagina. In addition, high levels of androgens during fetal development can lead to toxic effects such as reduced litter size and viability. The study of the effects of testosterone administration during sexual differentiation provides a foundation for understanding the effects of environmental androgens on fetuses, a sensitive subpopulation. In the current study, we investigated the ability of a range of concentrations of testosterone propionate (TP) administered prenatally to masculinize female and alter male offspring, and measured maternal and fetal T levels. Pregnant Sprague-Dawley rats were dosed by sc injection on gestational day (GD) 14-19 (GD 1= day of plug) with either corn oil (vehicle; 0.1 ml/rat) or with 0.1 ml of TP solution at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml. Parturition was delayed at 2, 5, and 10 mg TP, litter size was reduced at 5 and 10 mg TP, and pup weight was significantly reduced in both sexes at 0.5 mg TP and higher doses. Viability of offspring was unaffected at any dosage level. Androgenic effects seen at 0.5 mg TP in females included increased AGD at weaning and adulthood, reduced number of areolas and nipples, cleft phallus, small vaginal orifice, and presence of prostate tissue. This dose of TP elevated maternal T levels 10x but had no effect on fetal T levels. At 1 mg TP and above, female AGD on postnatal day (PND) 2 (or postcoital day 24 [gestation length = 22(1/2)]) was increased; areolas and nipples were virtually eliminated; levator ani muscle, bulbourethral glands, and seminal vesicles (2 mg TP and above) were present; none of the females developed a vaginal orifice and many females in the 1 and 2 mg TP dose groups developed a greatly distended, fluid-filled uterus after puberty. Maternal T levels at 1 mg TP were elevated 30x, and female fetal T levels showed an 80% increase. Male offspring displayed a reduced AGD and body weight on PND 2 at 0.5 mg TP and higher doses. These effects were not evident by weaning and male offspring displayed no malformations. We conclude that gestational administration of 0.5 and 1 mg TP masculinizes female offspring without greatly affecting pup viability or pregnancy of the dam. This study provides a useful model for in utero testing of environmental androgens for their potential to induce developmental abnormalities.     

The impact of oral exposure to low-dose tris(2-butoxyethyl) phosphate in allergic asthmatic mice

Tris(2-butoxyethyl) phosphate (TBEP) is a major organophosphorus flame retardant and has been widely increasing as a substitute for brominated flame retardants. TBEP may have adverse effects on human health; however, its impact on immune and allergic responses remains largely uncharacterized. In this study, the effects of low-dose TBEP comparable with the level of actual human exposure to that of human tolerable daily intake on allergic asthmatic mice were explored. Five-week-old C3H/HeJSlc male mice consumed a diet containing approximately 0.02, 0.2 or 2 μg/kg/day TBEP and were intratracheally administrated ovalbumin (OVA) (1 μg/mouse every 2 weeks from 5 to 11 weeks of age). Exposure to 2 μg/kg/day TBEP with OVA tended to enhance allergic pulmonary inflammation and significantly elevated mRNA levels of interleukin-5, eotaxin-1 and estrogen receptor alpha (ERα) compared with OVA alone. In mediastinal lymph nodes (MLNs), TBEP (0.2 or 2 μg/kg/day) with OVA significantly increased in total cell number and promoted conventional dendritic cell activation than OVA alone; MLN cell proliferation by OVA restimulation was also enhanced in these groups. In the bone marrow (BM), TBEP (0.02 or 0.2 μg/kg/day) with OVA resulted in a net decrease in total cell number and fraction of CCR2⁺Gr-1⁺ cells; the fraction of Gr-1⁺ cells increased. In conclusion, oral exposure to low-dose TBEP levels equivalent to tolerable daily intake may exacerbate allergic pulmonary inflammation by promoting a skewed T-helper 2 cell response, upregulation of ERα and dysregulation of both MLN and BM microenvironments.     

Neurologic and immunologic effects of exposure to corticosterone, chlorpyrifos, and multiple doses of tri-ortho-tolyl phosphate over a 28-day period in rats

An animal (rat) model of chronic stress (corticosterone in the drinking water) was used to study the interaction of stress and the organophosphorus (OP) neurotoxicants chlorpyrifos (60 mg/kg subcutaneously in a single dose) and tri-ortho-tolyl phosphate (TOTP, at 75, 150, or 300 mg/kg given 7 times orally in a 2-wk period). Adult male Long-Evans rats were provided with corticosterone in drinking water (400 microg/ml, w/v) for a total of 28 d, which led to significantly decreased weight and decreased cellularity of the thymus and spleen. Seven days after initiation of corticosterone treatment, half of the rats were given chlorpyrifos, and an additional 7 d later the 2-wk, 7-dose treatment of TOTP was initiated. During the 28-d test period, behavior of rats was evaluated using a functional observational battery (FOB), motor activity, and passive avoidance. Reductions in body weight, grip strength, and ambulatory movements occurred as a result of corticosterone treatment. Decreased body weight and grip strength were also elicited by TOTP, and the interactions of corticosterone and TOTP enhanced the effects on body weight and grip strength. Blood cholinesterase levels were obtained during the 28-d study period and found useful for monitoring OP exposure. At the end of the 28-d testing period, rats were sacrificed and activities of cholinesterase, neurotoxic esterase (neuropathy target esterase), and/or carboxylesterase were evaluated in blood, liver, and/or brain regions (basal forebrain, caudate putamen, cerebral cortex, hippocampus). All these esterases in brain were inhibited in a dose-related manner by TOTP, with some enhancement in rats drinking corticosterone-containing water. In addition, choline acetyltransferase, glial acidic fibrillary protein (GFAP), glutathione peroxidase, and superoxide dismutase were evaluated in one or more of the brain regions already identified. Choline acetyltransferase, glutathione peroxidase, and superoxide dismutase activities were unaffected by treatments. However, GFAP was elevated above control levels in the cerebral cortex of rats by all treatments (corticosterone, chlorpyrifos, TOTP). Neuropathological examination revealed early stages of dose-related increased distal myelinated fiber axonal degeneration seen in the medullary fasciculus gracilis at only the highest dose of TOTP (300 mg/kg).     

Effect of exposure to fluoride and acetaminophen on oxidative/nitrosative status of liver and kidney in male and female rats

BackgroundThis study was undertaken to investigate, the effect of 6 weeks treatment with acetaminophen (AAP) and fluoride (F), administered either separately or together, on nitric oxide generation, lipid and protein peroxidation, total antioxidant status and level of reduced glutathione in the liver and kidney of male and female Wistar Han rats. Also, the influence of AAP on F excretion in urine was determined.MethodsThirty adult male and female rats were divided into five equal groups of six each: (I) controls drinking tap water; (II) controls drinking tap water and receiving 1 ml of tap water intragastrically; (III) animals receiving 12 mg F/L in drinking water; (IV) animals receiving 150 mg AAP/kg b.w./day; (V) animals receiving 12 mg F/L in drinking water and 150 mg AAP/kg b.w./day.ResultsF and AAP given separately and both together enhanced oxidative and nitrosative stress in investigated tissues. No gender differences were observed in oxidative/nitrosative stress parameters during treatment with F and/or AAP. Interestingly, the combined exposure to F and AAP resulted in an enhancement of oxidative/nitrosative stress in kidney of male and female rats compared to the group treated separately with F and AAP. No additive effect in the measured parameters in the liver during co-exposure to both xenobiotics was noticed.ConclusionsAs expected, the urinary F excretion increased in an exposure time-dependent manner in rats receiving F or a combination of F and AAP. The study also showed that AAP significantly decreased urinary F.     

Effects of a histamine synthesis inhibitor and antihistamines on the sexual behavior of female rats

Intraventricular administration of -hydrazinohistidine, a histamine synthesis inhibitor, at different doses and times before testing produced a significant decrease of lordotic responses and sexual receptivity in ovariectomized estrogen plus progesterone-primed female rats. The H₁-antihistamines pyrilamine and chlorfeniramine and the H₂-antihistamine metiamide, injected in the lateral ventricle, significantly decreased the lordosis quotient but did not modify receptivity; antihistamine-injected rats showed no soliciting behavior. Exploratory activity was decreased by both -hydrazinohistidine and metiamide but not by the H₁-antihistamines. It is concluded that treatments which either deplete histamine or block their receptors can alter female copulatory responsiveness. The mechanism of this antihistamine effect appears to be unrelated to that of other side effects, such as motor impairment, sedation, or local anesthesia.     

Disposition of the emerging brominated flame retardant,bis(2-ethylhexyl) tetrabromophthalate,in female Sprague Dawley rats: effects of dose,route and repeated administration

1.?Bis(2-ethylhexyl)-tetrabromophthalate (BEH-TEBP; CAS No. 26040-51-7; PubChem CID: 117291; MW 706.15?g/mol, elsewhere: TeBrDEPH, TBPH, or BEHTBP) is used as an additive brominated flame retardant in consumer products.

2.?Female Sprague Dawley rats eliminated 92–98% of [¹⁴C]-BEH-TEBP unchanged in feces after oral administration (0.1 or 10?μmol/kg). A minor amount of each dose (0.8–1%) was found in urine after 72?h. Disposition of orally administered BEH-TEBP in male B6C3F1/Tac mice was similar to female rats.

3.?Bioaccumulation of [¹⁴C]-radioactivity was observed in liver and adrenals following 10 daily oral administrations (0.1?μmol/kg/day). These tissues contained 5- and 10-fold higher concentrations of [¹⁴C]-radioactivity, respectively, versus a single dose.

4.?IV-administered [¹⁴C]-BEH-TEBP (0.1?μmol/kg) was slowly eliminated in feces, with?>15% retained in tissues after 72?h. Bile and fecal extracts from these rats contained the metabolite mono-ethylhexyl tetrabromophthalate (TBMEHP).

5.?BEH-TEBP was poorly absorbed, minimally metabolized and eliminated mostly by the fecal route after oral administration. Repeated exposure to BEH-TEBP led to accumulation in some tissues. The toxicological significance of this effect remains to be determined. This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health (Project ZIA BC 011476).     

The effects of prenatal exposure to atrazine on pubertal and postnatal reproductive indices in the female rat

Atrazine (ATR) is an herbicide that exerts negative reproductive effects. We examined the effects of vehicle or ATR (1, 5, 20 and 100 mg/kg-d), administered to Sprague-Dawley rats on gestational days 14-21, once daily or divided into two doses per day, on female offspring reproductive indices. Offspring body weights at birth were reduced and mortality increased in the 100 mg/kg-d group shortly after birth; by PND 21 there were no significant effects. Vaginal opening was delayed in this group, indicating delayed puberty. No significant differences in mammary gland development were apparent at PND 45, or estrous cyclicity through PND 272. There were no differences between dosing regimens. Lower ATR doses (0-20 mg/kg-d) showed few effects in females prenatally exposed to ATR, while the high dose (100 mg/kg-d) reduced offspring body weight and delayed vaginal opening. Nonetheless, it is unlikely that environmental exposure comparable to the high dose would be encountered.     

Effects of perinatal combined exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and tributyltin (TBT) on rat female reproductive system

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p′-DDE) is the most prevalent metabolite of DDT used as a pesticide before and tributyltin (TBT) compounds are used primarily as antifouling agents on vessels, ships, and aqua culture facilities, as they exert biocidal actions. Currently, p,p′-DDE and TBT are ubiquitously distributed in the environment and bio-accumulated in marine products, especially fish or shellfish. Thus, oral p,p′-DDE and TBT intake through marine products is demonstrated to be rather high in Japan. Consequently, the fetus and neonate will be exposed to p,p′-DDE and TBT via mother. Therefore, effects of perinatal combined exposure to p,p′-DDE and TBT on the female reproductive system after maturation have been investigated in rat female offspring of dams ingesting 125 ppm p,p′-DDE (approximately 10 mg/kg) and 25 ppm TBT (approximately 2 mg/kg) during the perinatal period from gestation to lactation. In the present study, no deleterious reproductive outcomes were recognized in p,p′-DDE and/or TBT-treated dams. In contrast, growth retardation had developed in rat female offspring following perinatal exposure to TBT and sustained even after cessation of exposures. Further, reduced ovarian weights with elevated serum follicle-stimulating hormone (FSH) concentrations were observed in the reproductive system of matured female offspring following perinatal exposure to TBT. At present, biological relevance of these alterations remains unknown, but there is a possibility that these alterations lead to reproductive malfunctions in matured female offspring.     

The effects of maternal exposure to food additive E341 (tricalcium phosphate) on foetal development of rats

E341 (tricalcium phosphate) (TCP) is commonly used as a food additive and also as a nutritional supplement. To evaluate the possible developmental effects, female Wistar rats were treated with E341 (TCP) by oral gavage during pregnancy. There were three groups of each containing five rats. Rats in Groups I-III were fed with standard diet, oil and E341 (TCP) 175mg/kg body weight during gestation days (GD 0-20) respectively. We assessed foetal body lengths and weights and also made morphometric examination of placenta and umbilical cord. The placental weights of E341 (TCP) group (Group III) were found to be decreased statistically. According to skeletal stainings of foetuses, lengths of left ulna (28.3%), right femur (29.8%), left femur (34.9%) and diameter of the skull of y-axis were significantly decreased (12.3%) in E341 (TCP) treatment groups. There was an increase in trans-umbilical diameter in treatment group (14%). This is the first study in which developmental effects of E341 (TCP) have ever evaluated. The results suggest that prenatal development of rats during gestation is sensitive to E341 (TCP) exposure.