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Cadmium (Cd) is regarded as a potential endocrine disruptor. However, the exact mechanism by which this metal may interfere with the reproductive system has not yet been elucidated. The present study aimed to investigate the effect of subacute Cd oral administration at daily doses of 0.09, 1.8, and 4.5 mgCd/kg b.w. and the impact of Cd on sex hormones (estradiol (E2) and progesterone (P)) in the plasma and uterus, as well as on estrous cyclicity and histopathological changes in uterine and ovary in female rats after terminating the exposure and after a prolonged observation period (3 months). Moreover, Cd bioaccumulation in the uterine and brain tissue of rats was analyzed. The study revealed that oral Cd exposure induced changes in the plasma levels of steroid hormones: decrease in E2 and increase in P after the highest dose of Cd. Probably, for the first time, it was evidenced that circulation sex hormone disturbances in Cd-exposed rats caused irregular estrous cycle, persisting for 3 months after exposure termination; no alterations in these hormone levels in uterine tissue were noted. Cd did not induce estradiol-like hyperplasia of endometrium, but resulted in endometrial edema irrespective of the dose, and caused damage of the ovaries after the highest dose. In summary, subacute oral exposure of female rats to Cd may lead to long-term disturbances in reproductive system.

Objectives: The objective of the study was to assess prenatal toxicity of N-methylaniline (NMA) administered by gavage to pregnant female rats. Material and Methods: Pregnant female rats were administered N-methylaniline in corn oil by gavage at daily doses of 0.8 mg/kg of body weight (b.w.), 4 mg/kg b.w., 20 mg/kg b.w. and 100 mg/kg b.w. from implantation (the 5th day post mating) to the day prior to the scheduled caesarean section (the 20th day of pregnancy). General behavior, body weight, food and water consumption, hematological, biochemical analyses and pathomorphological changes of the dams were recorded. Results: All the females survived until the end of the study. The test substance was toxic to pregnant females, even at the lowest of the used doses, i.e., 0.8 mg/kg b.w./day. Lower weight gain during pregnancy and significantly higher NMA-dose-dependent absolute weight of the organs were noted in the exposed females. The females from the groups exposed at doses of 20 mg/kg b.w./day and 100 mg/kg b.w./day developed anemia and showed higher concentrations of free thyroxine (FT3) and free triiodothyronine (FT4) thyroid hormones. Total protein concentration exhibited an increase in all the exposed groups of females. In the prenatal toxicity study, administration of N-methylaniline throughout the embryonic and fetal periods produced embryotoxic effects at doses ranging 4–100 mg/kg b.w./day. Conclusions: Considering the data obtained in this study, it is reasonable to assume that N-methylaniline administered orally to pregnant rats is toxic for mothers even at a low dose of 0.8 mg/kg b.w./day. However, this dose was not associated with any significant effects to their offspring. This prenatal exposure level may be considered as no-observed-adverse-effect level (NOAEL) for the progeny and a dose of 4 mg/kg b.w./day as the lowest-observed-adverse-effect level (LOAEL) for the progeny. “Assessment of prenatal toxicity of rats exposed intragastrically to N-methylaniline,” project IMP No. 1.9.

Objectives Due to structural and toxicological similarities to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated naphthalenes (PCNs) were included in the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2015. Hexachloronaphthalene (HxCN) is considered to be one of the most toxic congeners of PCNs. The objective of this study was to determine the maternal and fetal tissue concentrations of hexachloronaphthalene after a single administration. Material and methods Pregnant female Outbred Wistar rats were used for the study. The [14C]-HxCN was administered in a single oral dose of 0.3 mg/rat (150 kBq/rat) on gestational day 17 (GD17), GD18 or GD19. All dams were sacrificed on GD20. The blood and selected tissue samples taken from mothers and fetuses 24 h, 48 h or 72 h after exposure were evaluated for the distribution of HxCN. Results Maximum concentrations of HxCN in pregnant rats were found in the liver and adipose tissue. Relatively high levels of HxCN were also reported in the spleen, ovaries, adrenal glands and uterus, as well as in the sciatic nerve, brain and kidneys. Hexachloronaphthalene penetrates through the blood-brain barrier (BBB), as evidenced by twice the concentration in the brain compared to the blood concentration, and through the placental barrier, as indicated by the level of maternal-fetal compartment (placenta, amniotic fluid, litter). Among the examined fetal tissues, the highest levels of HxCN were found in the kidneys and in the brain. The concentrations in these organs were higher than that found in the maternal blood. Conclusions This paper is the first to detail the concentrations of HxCN in the maternal tissues and the transplacental transfer of the tested compound to the fetuses. The exposure of pregnant rats to HxCN results in its accumulation in the maternal liver, fat tissue, reproductive and nervous system, and particularly in the fetal brain. This demonstrates both the effective absorption and significant systemic accumulation which could lead to negative health implications. Int J Occup Med Environ Health 2018;31(5):685-695.

Hexachloronaphthalene (HxCN) is one of the most toxic congeners of polychlorinated naphthalenes (PCNs). This study assesses the prenatal toxicity of HxCN after daily administration at doses of 0.1-1.0mg/kg b.w. to pregnant Wistar rats during organogenesis. We evaluated also the expression of CYP1A1 mRNA and protein in the livers of dams and fetuses, as well as the placenta. The results indicate that 0.3mg/kg b.w. was the lowest HxCN toxic dose for dams (LOAEL) while a dose of 0.1mg/kg b.w. was sufficient to impair the intrauterine development of embryos/fetuses without maternal toxicity. Regardless of the applied dose, HxCN generated embryotoxic effects. Dose-dependent fetotoxic effects were associated with HxCN exposure. HxCN was found to be a strong inducer of maternal and fetal CYP1A1. Expression of CYP1A1 mRNA in the placenta appears to be the most sensitive marker of HxCN exposure.

The aim of the study was to assess the maternal toxicity of polychlorinated naphthalenes (PCNs) and embryotoxic, fetotoxic, and teratogenic effects after administration of the PCN mixture to pregnant rats in four (0.3-9.0 mg/kg bw) daily doses during organogenesis (days 6-15 of gestation). For dams, a dose of 0.3 mg/kg bw, administered during organogenesis, has been established as NOAEL of PCNs, and a dose of 1 mg/kg bw, administered in the same period, as LOAEL. The dose-related fetotoxic (reduced body weight and length of the fetus, extension of renal pelvis and lateral brain ventricles, signs of delayed ossification and retardation in development of internal organs), and teratogenic effects (cleft palate and hydronephrosis) were recorded at all dose levels, also at the dose non-toxic to mothers. PCNs have been concluded to be potent fetotoxic and teratogenic agents producing similar effects to those of other toxic dioxin-like compounds.

Sulfenamide TS (N-cyclohexyl-2-benzothiazolesulfenamide), accelerator of rubber vulcanization, was administered to female rats by gavage at doses of 50, 150, and 450 mg/kg (1%, 3%, and 8% of LD50) during organogenesis. The maternal toxicity of Sulfenamide TS was found at the highest dose of 450 mg/kg. Oral administration of this compound to female rats during organogenesis induced fetotoxic effects at doses of 50 mg/kg and higher. The dose-dependent increase in the frequency of fetuses/ litters with internal hydrocephalus was observed.

The solvent, dimethylene glycol monobutyl ether (DGBE), is a component of latex paints, inks; it is used as a degreasing agent, industrial detergent. The aim of the study was evaluating the effects of DGBE administered by gavage on the estrous cycle and given with drinking water on fertility in rats and early development of their progeny. Female rats were exposed to DGBE by gavage during 8 weeks at 250, 500 or 1000 mg/kg/day. Vaginal smears were collected during the exposure and 4 weeks after its cessation. Fertility studies were performed in male and female animals exposed to in drinking water. Males were exposed for 10 weeks and then mated with females exposed before mating, during pregnancy and lactation. Young animals were observed during 3 weeks after birth. DGBE does not cause disturbances of the menstrual cycle in females. Parameters used to assess the general toxicity indicate that males receiving DGBE in drinking water are more sensitive to this compound than females: significantly greater, dose-dependent relative spleen weight, significant decrease in hematological parameters from 8% to 15% depending on the dose, were observed. Clinical chemistry parameters (HDL-cholesterol, BUN) and some markers of oxidative stress differ between the exposed groups and the control one, but without adverse health effect. The microscopic examination of internal organs did not reveal morphological changes in male and female rats. The results of our study on the impact of exposure to DGBE on fertility in rats indicate that the substance administered for 9–10 weeks to females and males at a limit dose of 1000 mg/kg did not impair fertility or viability of their offspring during the first three weeks of life.

N-methyl-2-pyrrolidone (NMP) is a solvent used in the petrochemical, and electronic industries, in pesticides production, veterinary drugs, and paint removers. The aim of study was to evaluate the relationship between the dose of NMP given orally and its effect on fertility in female rats and early development of their progeny.Females were exposed by gavage 5 days/week to NMP at 150, 450, or 1000 mg/kg/day 2 weeks before mating, during mating, gestation, and lactation. On the first postnatal day (PND 1), the live and dead pups were counted, weighed, and gender was determined. On PND 4, the litters were culled to eight animals each and balanced for gender. Young animals were observed during 3 weeks after birth.Fertility index did not significantly differ in the control and the group exposed at 150 mg/kg/day but it was significantly lower in the groups exposed at 450 or 1000 mg/kg/day. The number of live pups in the group exposed to the highest dose was significantly lower and the number of stillbirths in litters was significantly greater. Survival of the pups from all exposed groups during the 3 weeks after birth was significantly lower than the control animals. The results of our study indicate that intragastric exposure of female rats to NMP before pregnancy during gestation causes significant impairment in female fertility and intrauterine mortality rates. At lower doses, toxic or slightly toxic to the mothers, this substance causes decrease in viability and physical development of progeny.

Objective: The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a widespread, man-made, persistent organic pollutant with high immunotoxic potentials. It suppresses cell-mediated and humoral immune responses through mechanisms dependent on aryl-hydrocarbon receptor expression and immunosuppressive activity of the cells. Most sensitive to TCDD are organisms during fetal and infant life, mostly due to the developmental stage of many biological systems of the host, including immune system. Recent data show that T regulatory cells that have the potential to suppress immune reactions and which develop after TCDD exposure are also responsible for protection from allergy development. Our goal was to investigate if perinatal exposure to TCDD can affect allergic sensitisation and if T reg cells participate in this phenomenon. Materials and Methods: Mice, Balb/c, were perinatally exposed to TCDD or to the carrier. Six weeks old control or exposed mice were sensitised with ovalbumin. Spleen cells of the animals were used to assess the constent of T reg cells by means of flow cytometry. Levels of cytokines were assessed by ELISA technique in supernatants of the cells stimulated with anti-CD3 antibody. As a measure of sensitisation, total IgE and anti-OVA IgE were measured in serum of mice by ELISA method. To assess the function of T reg cells isolated from OVA-sensitised control or TCDD exposed animals we performed transfer studies. Results: Here we show that perinatal exposure to TCDD decreases allergic sensitisation and that this process is related to inhibition of IL-4 synthesis rather than suppression mediated by T regulatory cells. Conclusion: We hypothesise that dioxin exposure can be an important environmental modulator of immunological responses that participate in allergic reactions.

Objectives: Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants. Both are neurotoxic, especially for the developing brain. The main source of human exposure to MeHg and PCBs is seafood. The aim of the present work was to find out whether and how separate or combined perinatal exposure to these neurotoxicants affects neurobehavioural functions in maturity. Materials and Methods: The study was performed on adult Wistar rats, the progeny of rat mothers exposed to MeHg (0.5 mg/kg/day or 2.0 mg/kg/day), PCB 153 (1.0 mg/kg/day or 5.0 mg/kg/day), or to MeHg 0.5 mg/kg/day + PCB 153 5.0 mg/kg/day, from day 7 of pregnancy to day 21 post partum. The following functions were assessed: spontaneous locomotor activity (open field test), spatial short-term memory (radial maze test), long-term memory (passive avoidance test), sensitivity to pain and vulnerability to stress (hot plate test), efficiency of the sensorimotor gating (startle response test), and sensorimotor coordination (the rotarod test). Results: The results obtained in the MeHg part of the study showed a reduced locomotor activity in the female progeny of both exposed groups, an impaired passive avoidance in the male progeny of the high and low exposure group and a faster recovery from the effects of the stressful experience (hot plate test) in the male progeny of the high dose group. Results obtained in the PCB part showed an increased locomotor activity in the female progeny of both exposure groups and impairment in rotarod performance in males of the high dose group. Neurobehavioural alterations were not found in either the females or males exposed jointly to MeHg and PCB 153. Conclusions: The results suggest that in condition of the combined exposure, MeHg may protect against the effects of PCB 153 and vice versa.

Objectives: Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are ubiquitous and persistent environmental pol-lutants and food contaminants. Both are neurotoxic, especially for the developing nervous system. Material and Methods: Female rats were exposed from day 7 of pregnancy up to day 21 after the delivery to MeHg in drinking water, PCB 153 per os or MeHg+PCB 153. Assessment of the exposure effects in mothers included food and water intake, body weight and reproduction success. Assessment of the progeny comprised determination of body weight, time of pinna detachment, eye opening, incisor eruption, and the negative geotaxis, grip strength and righting reflex. Results: The following effects of the exposures were observed: A) MeHg: 0.5 mg/kg/day — no effect on maternal health status and reproduction. In the progeny: faster incisor eruption and hastened negative geotaxis development. MeHg 2.0 mg/kg/day: In mothers: signs of MeHg toxic-ity (reduced food intake and body weight, ataxia) during lactation. In the progeny: reduced rate of body weight increase, accelerated incisor eruption but delayed development of the righting reflex.B) PCB 153 exposure: 1.0 mg/kg/day: no effect on maternal health status, reproduction success or morphological and physical development of the progeny; 5.0 mg/kg/day: no effect on maternal health status and reproduction. In the progeny: accelerated growth in females, faster pinna detach-ment and incisor eruption but delayed development of the grip strength. C) MeHg+PCB153 exposure: none overt effect was noted in mothers or in their progeny. Conclusion: The results confirmthe ability of a low level perinatal exposure to MeHg or PCB 153 to affect the early development in the rat. They have not provided, however, an evidence of a synergistic interaction of these contaminants. To the contrary, the results suggest that, at least under the conditions prevailing in the present study, MeHg and PCB 153 interact antagonistically.

Objectives: N-methyl-2-pyrrolidone (NMP) is a solvent used in petrochemical, electric and electronic industries, and in the production of paint removers, pesticides and veterinary drugs. The substance exhibits slight acute toxicity, and moderate irritant, embryotoxic and teratogenic effects. The aim of the study was to assess NMP reproductive toxicity and gonadotoxicity in male rats. Material and Methods: The animals were exposed per os to NMP at daily doses of 0, 100, 300 and 1000 mg/kg. After 10 weeks of exposure, each male was mated with nonexposed female, then all the males were autopsied, and epididymis and testis were fi xed for pathomorphological examination. Viability and development of offspring was observed to 28 days postbirth. Results: NMP at 1000 mg/kg was found to produce male infertility and extensive damage to the seminiferous epithelium in the seminal tubules of the testis. When administered at 100 mg/kg or 300 mg/kg, it did not signifi cantly affect fertility or spermatogenesis. NMP exposure at 100 mg/kg did not infl uence either the viability or the development of their offspring in the fi rst month of life, while exposure at 300 mg/kg resulted in a signifi cantly lower viability of the offspring in the fi rst four days of life. Conclusion: This study has demonstrated that sub-chronic exposure of male rats to NMP at 1000 mg/kg/day produces gonadotoxic effect and brings about infertility. Administration at lower doses of 100 and 300 mg/kg did not impair male fertility, but only the lowest dose of 100 mg/kg was found to have no infl uence on the prenatal development of the progeny.

Objectives: N-methyl-2-pyrrolidone (NMP) belongs to solvents widely used in the petrochemical industry a well as in the production of pesticides, veterinary drugs and paint removers. NMP is easily absorbed from the respiratory tract, digestive system and through the skin. It is a compound of slight acute toxicity that also displays moderate irritating activity. The aim of this study was to assess tissue distribution and excretion following a single intraperitoneal NMP administration. Materials and Methods: Tissue distribution and excretion of NMP following administration of a single dose of 250 mg/kg body weight (350 kBq/rat) was investigated using 14 C. Blood plasma (6 rats per time point) were sampled up to 72 h after administration and determination of radioactivity. Male and female rats (4 animals per time point) were decapitated at appropriate time intervals and examined tissues were removed for determination of radioactivity. Excretion of 14 C in urine and feces were also measured. All radioactivity measurements were carried out using a Rackbetta 1209 (LKB, Sweden) liquid scintillation counter. Results: The highest 14 C activity in tissues and internal organs of female and male rats was observed 4 h after administration of the compound. The highest accumulation was detected in the muscles and fat tissue as well as in the liver and testicles. During 72 h following administration, approximately 80% of the dose was excreted in urine. Elimination of the compound in feces was far less significant: only about 5% of the dose was excreted at once. Conclusions: The results of the study indicate that there are no significant differences in 14 C-NMP tissue distribution between male and female rats; NMP absorption from the peritoneal cavity to blood is rapid, disappearance from plasma is monophase and kidneys are the main route of excretion of NMP and/or its metabolites from the rat body after administration of a dose equal to 10% of LD 50 . The ability to accumulate NMP and/or its metabolites in testes and seminal vesicles may be the reason for fertility impairment in male rats observed after repeated exposure to this compound.

This study was performed to evaluate the effects of prenatal development of rats were exposed to Polnoks R and its monomer 2,2,4-trimethyl-1,2-dihydroquinoline (TMDHQ) by gavage every day on days 6-15 of gestation at doses equivalent 6%, 13% and 25% of LD50. Polnoks R and TMDHQ administered per os associated with significant maternal toxicity, embryonal lethality, retarded fetal development and congenital defects. Polnoks R induced skeletal malformations, internal hydrocephalus, and hydronephrosis. 2,2,4-trimethyl-1,2-dihydroquinoline produced internal malformations (exencephale, hydrocephalus, anophthalmia, hydronephrosis and renal hypoplasia) and skeletal malformations of ribs and vertebrae. Polnoks R monomer--2,2,4-trimethyl-1,2-dihydroquinoline is used as an antioxidant in elastomer and rubber productions. Polnoks R and its monomer 2,2,4-trimethyl-1,2-dihydroquinoline are teratogenic to rats and induces CNS, kidneys and skeletal defects.

BACKGROUND: Polnoks R (poly-2,2,4-trimethyl-1,2-dihydroquinoline) is used as an antioxidant in elastomer processing. It is an embryotoxic and fetotoxic agent. This chemical given per os to female rats induces also teratogenic effect but only at doses toxic to the mother. The aim of the study was to evaluate prenatal development and tissue distribution in rats exposed to 2,2,4-trimethyl-1,2-dihydroquinoline (TMDHQ), a monomer of Polnoks R. METHODS: Females were exposed orally to unlabeled TMDHQ during organogenesis at doses 50–400 mg/kg to asses prenatal toxicity and to radiolabeled 14C monomer at a dose 210 mg/kg to evaluate tissues distribution. RESULTS: TMDHQ administered to pregnant females per os at doses 100 mg/kg and higher produced teratogenic effect (cleft palate, wavy ribs, kyphoscoliosis, exencephaly, external hydrocephalus, hydronephrosis, and renal hypoplasia). Peak 14C-radioactivity was found in mothers' plasma about 10 hr after administration of this compound at dose 210 mg/kg. The accretion of 14C proceeded with a kinetic constant of 0.35 hr −1 and a half-life of 53.3 hr. Kidneys are the main organs of monomer excretion. The highest concentration of 14C in maternal tissues 24 hr after oral dosing was found in adipose tissue, sciatic nerve, muscles, kidneys, and liver. Radiocarbon retention in fetuses was the highest in kidneys at all time points after dosing. CONCLUSIONS: This study has demonstrated that transplacental exposure to Polnoks R monomer is teratogenic in rats. 14C retention in placenta, amniotic fluid, and fetal tissues indicates that this compound or its metabolites penetrate into placenta to the fetus. Birth Defects Res B 68:375–382, 2003. © 2003 Wiley-Liss, Inc.

This study was performed to evaluate the effects of prenatal development of rats. Females were exposed to carbendazim by gavage every day on days 6-15 of gestation at doses 8, 35, 160 mg/kg b.w. Carbendazim administered at doses of 35 and 160 mg/kg was associated with significant maternal toxicity, embryonal lethality, congenital defects, and retarded fetal development. It produced encephalocele, umbilical hernia, missing or shorter tail, and internal malformations of brain, kidneys, and skeletal malformations of ribs, arch, and vertebrae. NOEL for the dam and fetus in our study was 8 mg/kg/day.

N-methylmorpholine, which is used as a catalyst in polyurethane foams producing, in solvents, stabilizing agents, and corrosion inhibitors, was administered to female rats by gavage at 100, 200, 600, and 900 mg/kg during organogenesis. It did not exhibit selective toxicity toward the developing conceptus. This compound administered to pregnant females was fetotoxic and teratogenic in the presence of maternal toxicity. N-methylmorpholine induced anophthalmia, internal hydrocephalus, and hydronephrosis but only at one dose which was also maternotoxic. Teratogenesis Carcinog. Mutagen. 19:369-376, 1999.

Cadmium chloride was administered by gavage to female rats 5 days a week for 5 weeks, then during mating and gestation periods at doses of 0.04, 0.4, and 4 mg Cd/kg/day. Treatment with cadmium neither affected the survival and fertility of females, nor produced overt fetotoxic effects. Fetal cadmium concentration was not related to the level of exposure. Litter size, body weight gain and viability of offspring during 2 months after parturition were similar in all groups. The exploratory locomotor activity of 2-month-old males and females born to rats given 0.4 and 4 mg Cd/kg/day was significantly reduced. The progeny of cadmium-treated females showed decreased performance in the rotarod test. In general, the degree of behavioral impairment was dose-related.

Female rats were administered by gavage an aqueous solution of CdCl2 for 14 weeks, 5 days per week, at doses of 0.04, 0.4, 4 and 40 mg Cd/kg/day or exposed by inhalation to CdO for 20 weeks (5 h per days, 5 days per week) at concentrations of 0.02, 0.16 and 1 mg Cd/m3. A pronounced increase in the mean duration of the oestrous cycle mainly due to lengthening of dioestrus was noted already 6 weeks after treatment of females given per os 40 mg Cd/kg or exposed to a concentration of 1 mg Cd/m3. No changes in the mean duration of the oestrous cycle were found in other experimental groups, although in the 0.16 mg Cd/m3 group an increased percentage of females with oestrous cycles lasting over 6 days was shown 18 weeks after exposure. Since Cd-induced lethality and decrease in body weight gain were observed in females given by gavage 40 mg Cd/kg or exposed by inhalation to a concentration of 1 mg Cd/m3, it is concluded that exposure to cadmium does not affect the sexual cycle unless other overt signs of Cd-toxicity are induced.