Maternal toxicity: a possible etiological factor in embryo-fetal deaths and fetal malformations of rodent-rabbit species

Data from animal teratology studies were surveyed to determine whether embryo-fetal mortality and fetal malformations result from a primary action of the agent on the conceptus or if they are secondary to maternal toxicity--a consequence of administration with high dose levels of test chemicals. A fairly strong association between embryo-fetal mortality and maternal toxicity was revealed by analysis of data from hamsters, mice, rats, and rabbits in 234 studies of chemical and physical agents, of which 83 were conducted at both maternotoxic and nonmaternotoxic doses, 94 only at maternotoxic doses, and 49 at nonmaternotoxic doses. In the above studies, only nine chemicals (four each in hamsters and rabbits and one in rats) were reported to induce embryo-fetal deaths at apparently nonmaternotoxic doses. These findings tend to suggest a contributory role for maternal toxicity in the induction of embryo-fetal deaths. The previously reported hypothesis that certain fetal defects in mice may perhaps be caused by maternal toxicity was also found to be true in a review of data on hamsters, rats, and rabbits. Salient maternal toxicity-associated fetal malformations were exencephaly, encephalocele, micro- or anophalmia, and fused ribs in hamsters and defective (fused, missing, or extra) ribs, vertebrae, and sternebrae, ex-, an-, or microphthalmia, and cleft palate in rats and rabbits. These malformations occurred at low frequencies, generally with no readily apparent dose-response relationship. Presumptive evidence indicates that embryo-fetal deaths, and the above-mentioned fetal malformations in experimental animals, which in published literature are presently attributed to chemical induction for a large number of chemicals, may be a consequence of maternal toxicity per se.     

The role of maternal toxicity in lovastatin-induced developmental toxicity

The role of maternal toxicity in lovastatin-induced developmental toxicity in rats was examined in a series of studies. The first study administered lovastatin at 100, 200, 400, or 800 mg/kg/day (mkd) orally to mated rats from Gestation Day (GD) 6 through 20. Maternal toxicity was observed as transient dose-related body weight losses at the initiation of dosing; there were also deaths and/or morbidity at 400 and 800 mkd. These toxicities occurred in conjunction with forestomach lesions. Mean fetal weights were decreased in all groups (-5 to -16%), and the incidence of skeletal malformations, variations, and incomplete ossifications was increased. The 2 highest doses produced the most severe maternal and developmental effects. Using the same dosages, the second study avoided gestational maternal weight losses and morbidity by starting treatment 14 days before mating with dosing continued to GD 20. There were transient dose-related body weight losses after the start of dosing and deaths in the 400- and 800-mkd groups; however, there was no evidence of maternal toxicity during gestation. Developmental toxicity was evident only as slight, but generally significant (p< or =0.05) decreases in mean fetal weights in groups given > or =200 mkd (-2 to -5%). Significantly, no skeletal abnormalities were observed. A third study administered the pharmacologically active metabolite of lovastatin subcutaneously at dose levels that matched oral maternal drug exposures. In the high-dose group, maternal weight gain and mean fetal weight were slightly decreased but there were no treatment-related skeletal abnormalities. Finally, a series of toxicokinetic studies assessed whether the 2 different developmental toxicity profiles were due to differences in drug exposure between the developmentally toxic and non-toxic dosing regimes. The data showed that groups with no skeletal abnormalities had maternal and embryonic/fetal drug concentrations similar to or even greater than the groups with fetal abnormalities. These results indicate that fetal skeletal abnormalities observed at lovastatin dose levels > or =100 mkd are not due to a direct teratogenic effect, but are the result of excessive maternal toxicity, which most likely involves a nutritional deficiency associated with forestomach lesions and reduced maternal food intake.     

Chemically induced alterations in maternal homeostasis and histology of conceptus: their etiologic significance in rat fetal anomalies

Possible relationships between maternal acid-base-electrolyte imbalance, histological changes in the maternal/extraembryonic tissues (decidua, placenta, membranes enclosing cavities), and fetal anomalies induced by maternotoxic doses of ethylene glycol, sodium salicylate, and cadmium chloride in rats were investigated. Acid-base-electrolyte, histologic and, teratologic studies were conducted concurrently with, as far as feasible, a similar protocol. Ethylene glycol caused 1) maternal homeostatic changes including metabolic acidosis and hyperosmolality, 2) extraembryonic lesions with degeneration of allantois and reduced villigenesis being more prevalent, and 3) materno-fetal effects such as decreases in fetal and maternal body weights, decreased maternal food intake, and fetal abnormalities (vertebral, rib, and sternebral defects). Few of these changes occurred when NaHCO3, an endogenous agent known to correct metabolic acidosis, was coadministered with ethylene glycol. Ethylene glycol-induced maternal metabolic acidosis, concurrent with hyperosmolality, was suspected to contribute toward reduction in villigenesis and fetal anomalies, including body weight reductions. Sodium salicylate induced the following: 1) mild maternal acidosis, hypokalemia, and hypophosphatemia with no significant change in pH; 2) maternal hemorrhage in extraembryonic cavities, papillary proliferation of the visceral yolk sac endoderm, and failure to form the chorioallantoic labyrinth; and 3) resorptions, hydrocephaly, rib defects, and fetal body weight reduction. Upon simultaneous treatment with sodium salicylate, NaHCO3 significantly reduced, and NH4Cl enhanced the incidence of the above histologic and teratologic effects, without significantly altering acid-base values. An etiologic association between the above salicylate-induced maternal and extraembryonic lesions and teratogenicity was likely. Cadmium chloride, whether administered by the intraperitoneal (ip) or intravenous (iv) route, caused 1) hydrocephaly, anophthalmia, vertebral and rib defects, reduction in fetal body weight, resorptions and maternal toxicity (acute peritonitis by the ip route only), and 2) extensive necrosis and hemorrhage in the decidua basalis, hemorrhage in the ectoplacental cone and around Reichert's membrane, and absence of chorioallantoic labyrinth. An etiologic relationship between these teratologic and histologic effects seemed probable, since both were dose-related. From the above studies, it was hypothesized that maternal factors--metabolic acidosis, hyperosmolality, hemorrhages in the ectoplacental cone, extraembryonic cavities, and around Reichert's membrane, and necrosis of decidua basalis--may have, directly or indirectly, reduced fetal nutrition and materno-embryonic gaseous exchange, which ultimately altered fetal development.     

Teratogenicity and developmental toxicity of valproic acid in rats

The teratogenicity and developmental toxicity of valproic acid (VPA) was investigated in Sprague-Dawley CD rats at doses of 0, 150, 200, 300, 400, and 600 mg/kg administered by gavage on days 7-18 of gestation. The VPA-600 dose was maternally toxic, causing death in two of four dams. This dose produced 100% embryonic resorption. The VPA-400 dose was maternally toxic in as much as maternal weight gain was reduced, but no deaths occurred. At this dose five of fifteen litters were completely resorbed, and 52% of all embryos were resorbed. Among survivors, 49% were malformed (68% having skeletal defects and 41% visceral defects). Fetal weight was reduced by 43% in this group. Most of the defects were ectrodactyly, hydronephrosis, cardiovascular defects, hypoplastic bladder, rib and vertebral defects, and other defects of the limbs and tail. The VPA-300 dose (nine litters) produced fewer defects, larger fetuses, and no increase in resorptions. The defects at this dose were primarily cariovascular, rib, and vertebral. The VPA-200 dose (12 litters) produced no reduction in fetal weight, no increase in resorptions, and few defects. The defects noted were hydronephrosis, cardiovascular abnormalities, and rib defects, primarily wavy ribs. Additional litters were prepared using doses of 150 and 200 mg/kg and were allowed to deliver and grow until 70 days. These doses produced no reduction in maternal weight gain, no reduction in litter size, birth weight, or sex ratio of the offspring. These doses produced no reduction in offspring weight to day 70, no increase in mortality, and only rare cases (two offspring of each dose) of tail defects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Developmental toxicity evaluation of berberine in rats and mice

BACKGROUND: Berberine, a plant alkaloid, is found in some herbal teas and health-related products. It is a component of goldenseal, an herbal supplement. Berberine chloride dihydrate (BCD) was evaluated for developmental toxicity in rats and mice. METHODS: Berberine chloride dihydrate was administered in the feed to timed-mated Sprague-Dawley (CD) rats (0, 3,625, 7,250, or 14,500 ppm; on gestational days [GD] 6-20), and Swiss Albino (CD-1) mice (0, 3,500, 5,250, or 7,000 ppm; on GD 6-17). Ingested doses were 0, 282, 531, and 1,313 mg/kg/day (rats) and 0, 569, 841, and 1,155 mg/kg/day (mice). RESULTS: There were no maternal deaths. The rat maternal lowest observed adverse effect level (LOAEL), based on reduced maternal weight gain, was 7,250 ppm. The rat developmental toxicity LOAEL, based on reduced fetal body weight per litter, was 14,500 ppm. In the mouse study, equivocal maternal and developmental toxicity LOAELs were 5,250 ppm. Due to scattering of feed in the high dose groups, a gavage study at 1,000 mg/kg/day was conducted in both species. CONCLUSIONS: In rats, maternal, but not fetal adverse effects were noted. The maternal toxicity LOAEL remained at 7,250 ppm (531 mg/kg/day) based on the feed study and the developmental toxicity NOAEL was raised to 1,000 mg/kg/day BCD based on the gavage study. In the mouse, 33% of the treated females died. Surviving animals had increased relative water intake, and average fetal body weight per litter decreased 5-6% with no change in live litter size. The maternal toxicity LOAEL remained at 5,250 ppm (841 mg/kg/day) BCD, based on increased water consumption. The developmental toxicity LOAEL was raised to 1,000 mg/kg/day BCD based on decreased fetal body weight.     

Developmental toxicity of the cyanogenic glycoside linamarin in the golden hamster

Cassava, a staple food in many tropical countries, has been suspected as a cause of human congenital defects. Ingestion of the material during pregnancy has been reported to induce limb defects, microcephaly, open eye, and growth retardation in rats. Linamarin is a natural cyanogenic glycoside that occurs in high concentrations in cassava. In the present study, pregnant hamsters received an oral dose of 70,100, 120 or 140 mg/kg linamarin or an equivalent volume of isotonic saline during the early primitive streak stage of gestation. A dose of 120 or 140 mg/kg of the glycoside was associated with an increased incidence of vertebral and rib anomalies as well as the production of encephaloceles in the offspring. These larger doses of linamarin also resulted in obvious maternal toxicity. Linamarin treatment had no effect on fetal body weight, ossification of fetal skeletons, embryonic mortality, or litter size. Although ingestion of the cyanogenic glycoside was associated with a significant teratogenic response, the effects occurred only at doses that elicited signs of maternal intoxication.     

Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy.

Bisphenol A (BPA) is an essential component of epoxy resins used in the lacquer lining of metal food cans, as a component of polycarbonates, and in dental sealants. The present study was conducted in an attempt to evaluate the adverse effects of the environmental estrogen BPA on initiation and maintenance of pregnancy and embryofetal development after maternal exposure during the entire period of pregnancy in Sprague-Dawley rats. The test chemical was administered by gavage to mated females from days 1 to 20 of gestation (sperm in varginal lavage = day 0) at dose levels of 0, 100, 300, and 1000 mg/kg. All females were subjected to caesarean section on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, significant toxic effects including abnormal clinical signs, decreased maternal body weight and body weight gain, and reduced food consumption were observed in pregnant rats. An increase in pregnancy failure was also found in the successfully mated females. In addition, increased number of embryonal deaths, increased postimplantation loss, reduced litter size and fetal body weight, and decreased number of fetal ossification centers of several skeletal districts were seen. On the contrary, no significant changes induced by BPA were detected in the number of corpora lutea and implantation sites and by fetal morphological examinations. In the 300 mg/kg group, suppressed maternal body weight and body weight gain, decreased food intake and reduced body weight of male fetuses were seen. There were no adverse signs of either maternal toxicity or developmental toxicity in the 100 mg/kg group. It was concluded that BPA administration during the entire period of pregnancy in rats produced pregnancy failure, pre- and postimplantation loss, fetal developmental delay and severe maternal toxicity, but no embryo-fetal dysmorphogenesis at an oral exposure level of 1000 mg/kg.     

Comparative effects of single intraperitoneal or oral doses of sodium arsenate or arsenic trioxide during in utero development.

Numerous studies have suggested that single-day intraperitoneal (IP) injection of inorganic arsenic results in failure of neural tube closure and other malformations in rats, hamsters, and mice. Most of these studies involved treatment of limited numbers of animals with maternally toxic doses of arsenic (generally As(V)), without defining a dose-response relationship. In the present Good Laboratory Practice-compliant study, sodium arsenate (As(V)) was administered IP and arsenic trioxide (As(III)) was administered either IP or orally (by gavage) on gestational day 9 to groups of 25 mated Crl:CD(R)(SD)BR rats. Only at dose levels that caused severe maternal toxicity, including lethality, did IP injection of arsenic trioxide produce neural tube and ocular defects; oral administration of higher doses of arsenic trioxide caused some maternal deaths but no treatment-related fetal malformations. In contrast, IP injection of similar amounts of sodium arsenate (based on the molar amount of arsenic) caused mild maternal toxicity but a large increase in malformations, including neural tube, eye, and jaw defects. In summary, neural tube and craniofacial defects were observed after IP injection of both As(V) and As(III); however, no increase in malformations was seen following oral administration of As(III), even at maternally lethal doses. These results demonstrate that the frequently cited association between prenatal exposure to inorganic arsenic and malformations in laboratory animals is dependent on a route of administration that is not appropriate for human risk assessment.     

Developmental toxicity of pentostatin (2'-deoxycoformycin) in rats and rabbits

The developmental toxicity of the potent adenosine deaminase (ADA) inhibitor, pentostatin (2'-deoxycoformycin), was investigated in pregnant rats and rabbits administered daily iv doses during organogenesis. Rats received 0, 0.01, 0.10, or 0.75 mg/kg on gestation days 6-15 and rabbits received 0, 0.005, 0.01, or 0.02 mg/kg on gestation days 6-18 and maternal and fetal parameters were evaluated on gestation day 21 (rats) or 30 (rabbits). Live fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal body weight gain and food consumption were significantly suppressed at doses of 0.10 and 0.75 mg/kg during the treatment period but returned to control levels during posttreatment. Increased postimplantation loss and decreased numbers of live fetuses, litter size, and fetal body weight were observed at 0.75 mg/kg. A statistically significant increase in the incidence of vertebral malformations occurred at 0.75 mg/kg. The incidence of certain skeletal variations (extra presacral vertebrae, extra ribs, hypoplastic vertebrae) was also increased at 0.75 mg/kg. Ossification of cervical centra was reduced at 0.75 mg/kg compared with controls. In rabbits, marked maternal toxicity (death, body weight loss, and decreased food consumption) and reproductive toxicity (abortion and premature delivery) occurred in all pentostatin-treated groups. However, there were no significant effects on number of live fetuses, pre- or postimplantation loss, litter size, or fetal body weights in the animals with live litters. There was also no apparent increase in the incidence of malformations or variations in the live fetuses of pentostatin-treated rabbits. Thus, these studies demonstrate developmental toxicity of pentostatin in rats and rabbits, and teratogenicity in rats, at maternally toxic doses.     

Deleterious effects of polynuclear aromatic hydrocarbon on blood vascular system of the rat fetus

BACKGROUND: Polynuclear aromatic hydrocarbons (PAH), benzo[alpha]pyrene (B[alpha]P) and 7,12-dimethylbenz[alpha]anthracene (DMBA) are toxic environmental agents distributed widely. The relative deleterious effects of these agents on growth and blood vasculature of fetus and placental tissues of the rat were studied. METHODS: Pregnant rats (Day 1 sperm positive) with implantation sites confirmed by laparotomy were treated intraperitoneally (i.p.) on Pregnancy Days 10, 12, and 14 with these agents dissolved in corn oil at cumulated total doses 50, 100, and 200 mg/kg/rat, and control with corn oil only (3-20 dams/group). Fetal growth, tissue hemorrhage, and placental pathology were evaluated by different parameters on Pregnancy Day (PD) 20 in treated and control rats. RESULTS: DMBA was relatively more deleterious compared to B[alpha]P indicated by increased lethality and progressive reduction of body weight of the mother with increasing doses. At 200 mg/kg/rat doses of these agents, maternal survival was 45% and 100% and body weight reduced 24% and 52% of controls, respectively. The fetal survival rates in live mothers were similar to that of controls. They induced marked fetal growth retardation and necrosis of placental tissues. B[alpha]P and DMBA produced significant toxicity to differentiating fetal blood vascular system as exhibited by rupture of blood vessels and hemorrhage, especially in the skin, cranial, and brain tissues. CONCLUSIONS: Maternal PAH exposure induced placental toxicity and associated adverse fetal development and hemorrhage in different parts of the fetal body, in particular, marked intradermal and cranial hemorrhage, showing that developing fetal blood vasculature is a target of PAH toxicity.     

Developmental Toxicity of the HMG‐CoA Reductase Inhibitor (PPD10558) in Rats and Rabbits

PPD10558 is an orally active, lipid‐lowering 3–hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor (statin) being developed as a treatment for hypercholesterolemia in patients who have not been able to tolerate statins because of statin‐associated myalgia. We have studied the potential developmental toxicity effects of PPD10558 in pregnant rats and rabbits given daily oral doses during the period of organogenesis. Rats were dosed with 0, 20, 80, or 320 mg/kg/day from Gestation Day (GD) 6 to 17 and rabbits received dose levels of 0, 12.5, 25, or 50 mg/kg/day from GD 6 to 18. Additional groups in both studies served as toxicokinetic animals and received the PPD10558 in the same manner as the main study groups at the same dose levels. Blood samples were collected from toxicokinetic animals at designated time points on GD 6 and 17 in rats and GD 6 and 18 in rabbits. Fetal exposure in rats was assessed on GD 20. Maternal and developmental parameters were evaluated in rats and rabbits on GD 20 and GD 29, respectively. No maternal and developmental toxicity was observed at any of the dose levels used in the rat study. Evidence of fetal exposure was determined in fetal plasma with mean fetal concentrations of PPD10558 and the metabolite (PPD11901) found to be between 1 and 6% of the mean maternal concentrations. In rabbits, marked maternal toxicity including mortality (eight deaths; 1 dose at 25 and 7 at 50 mg/kg/day), abortions (2 at 25 mg/kg/day and 6 at 50 mg/kg/day) and reduction in gestation body weight, gestation body weight changes and decreased food consumption were observed. In addition, fetal body weights of the combined sexes were significantly reduced at 50 mg/kg/day in comparison with the controls. Mean peak exposure (Cmax) and total exposure (AUC(0–24)) of PPD11901 in both rats and rabbits were higher than that of PPD10558 on GD 6 and GD 17 at each of the three dose levels.. Based on the results of these studies, the no observed adverse effect level (NOAEL) for maternal and developmental toxicity in rats was considered to be ≥320 mg/kg/day, the highest dose level used in the study. The NOAEL for maternal and developmental toxicity in rabbits was 12.5 mg/kg/day and 25 mg/kg/day, respectively.     

Comparison of the developmental toxicity of aspirin in rabbits when administered throughout organogenesis or during sensitive windows of development

BACKGROUND: A review of the nonsteroidal anti‐inflammatory drug (NSAID) literature suggested occurrences of low‐level incidences of cardiovascular and midline defects in rabbit fetuses exposed in utero. Aspirin (acetylsalicylic acid, ASA) is a widely used NSAID that irreversibly inhibits cyclooxygenases (COXs) 1 and 2. ASA has been studied extensively in rats and has consistently increased low‐incidence cardiovascular malformations and defects in midline closure. The objectives of the current study were to comprehensively define the developmental toxicology profile of ASA in rabbits by using a dosing paradigm encompassing the period of organogenesis and to test the hypothesis that maternal gastrointestinal toxicity after repeated dose administrations hampers the detection of low‐incidence malformations with ASA in rabbits by limiting ASA administration to sensitive windows for cardiovascular development and midline closure. METHODS: ASA was administered to pregnant New Zealand White rabbits from gestation days (GDs) 7 to 19 at dose levels of 125, 250, and 350 mg/kg per day and as single doses of 500, 750, or 1000 mg/kg on GD 9, 10, or 11. Cesarean sections were performed on GD 29, and the fetuses were examined for external, visceral, and skeletal development. RESULTS: In the repeated dose study, maternal toxicity was exhibited in the 250‐ and 350‐mg/kg per day groups by mortality and decreased food consumption and body weight gain. In the single dose studies, maternal toxicity was exhibited at all doses by reductions in body weight gain and food consumption for 3 days after treatment. Fetal body weight was significantly reduced in the repeated dose study at 350 mg/kg per day. Fetal weights were not affected by single doses of ASA on GD 9, 10, or 11. There were no treatment‐related external, visceral, or skeletal malformations associated with ASA administration throughout organogenesis or with single doses administered during critical developmental windows. CONCLUSION: These findings supported previous work demonstrating that ASA is not teratogenic in rabbits, as opposed to rats, even when large doses are administered on single days during specific windows of development. Birth Defects Research (Part B) 68:38–46, 2003. © 2003 Wiley‐Liss, Inc.     

Effects of an antisense oligonucleotide inhibitor of human ICAM-1 on fetal development in rabbits

The potential for reproductive toxicity of an antisense oligonucleotide designed to inhibit ICAM-1 was evaluated as part of the safety assessment for this compound. The human active ICAM-1 inhibitor (ISIS 2302) is not pharmacologically active in rabbits. Female rabbits were treated once daily on Day 6 through 18 of gestation. Rabbits were treated with 0, 1, 3, and 9 mg/kg ISIS 2302 by daily i.v. injection. Reproductive indices evaluated included estrus cycling, litter parameters, fetal development, and fetal body weight. Concentrations of oligonucleotide in plasma following the last dose, and in selected maternal target organs, placenta, and fetal tissues at scheduled necropsy were also measured. Maternal toxicity was evident as a decreased maternal body weight gain, decreased food consumption, and scant feces at doses > or =3 mg/kg. Increased spleen to body weight ratio and increased mononuclear cell infiltrates were indicative of a proinflammatory effect of ISIS 2302 at the 9 mg/kg dose level. Despite the maternal toxicity, there were no changes in litter parameters or fetal development in rabbits treated with ISIS 2302. The only change was a decrease in fetal body weight at the 9 mg/kg dose level, which was attributed to the maternal toxicity observed. Maternal liver and kidney contained dose-dependent concentrations of oligonucleotide, but there was relatively little or no oligonucleotide measured in placenta or fetal tissues. Thus, there was no dose-dependent exposure and maternal toxicity to ISIS 2302, but no reproductive toxicity in rabbits, and exposure of fetus or pups is negligible.     

Developmental effects of fumonisin B1 in mice

Developmental and toxic effects of aqueous extracts of F. moniliforme culture material containing known levels of fumonisin B₁ were recently reported in mice and included maternal hepatotoxicity and lethality, maternal body weight gain reduction, increased embryonic resorptions, reduced offspring body weights, and fetal malformations including cleft palate, hydrocephalus, malformed ribs and incomplete digital and sternal ossification. These studies also suggested that the effects of the fungal extract on the mouse offspring may be mediated via maternal effects. The contribution of fumonisin B₁ (FB₁), a major toxic metabolite of F moniliforme, in the induction of these effects was evaluated in this study by administering 0 to 100 mg pure FB₁/kg of body weight on gestational days (GD) 7 through 15 to pregnant Charles River CD1 mice and assessing maternal health and fetal development till the end of gestation. Doses of 25 mg/kg or higher of pure FB₁ induced maternal liver lesions (mostly necrotic changes), associated with ascites and increased hepatocytic nuclear diameter. Fumonisin doses of 50 mg/kg or higher also resulted in significantly increased maternal ALT on GD12, and reduced offspring bodyweights on GD 18. Increased resorptions and decreased numbers of live offspring were only evident at 100 mg FB₁/kg body weight. Offspring exhibited dose-dependent increase in the incidence and severity of hydrocephalus of both the lateral and third ventricles at doses of 25 mg/kg or higher. Doses of 25 mg/kg or higher also increased the sphinganine/sphingosine (Sa/So) ratios in maternal but not fetal livers. These results suggest that FB₁ may be a developmental toxicant accounting for most but not all earlier reported effects of F. moniliforme culture extract. Association of FB₁ effects on the offspring with maternal hepatoxicity and with alteration of Sa/So ratio in maternal but not fetal liver supported the earlier claim that FB₁ effects on the mouse offspring are mediated by maternal hepatotoxicity.     

Interactions in developmental toxicology: combined action of restraint stress, caffeine, and aspirin in pregnant mice

BACKGROUND: Stress can result in an increased use of substances such as caffeine and aspirin. The effect of maternal stress on concurrent exposure to caffeine and aspirin on prenatal development was assessed in mice. METHODS: On gestational day 9, mice were assigned to three treatment groups orally exposed to caffeine (30 mg/kg), aspirin (250 mg/kg), or a combination of caffeine (30 mg/kg) and aspirin (250 mg/kg). Three additional groups of pregnant animals received similar caffeine and aspirin doses and were immediately subjected to restraint for 14 hr. Control groups included unrestrained and restrained pregnant mice not exposed to caffeine or aspirin. All dams were euthanized on gestational day 18. Live fetuses were evaluated for sex, body weight, and external, internal, and skeletal malformations and variations. RESULTS: A single oral dose of caffeine or aspirin did not cause significant maternal toxicity. However, coadministration of these drugs with restraint produced some adverse maternal effects (i.e., reduction in maternal weight gain and food consumption on gestational days 9-11). In relation to embryo/fetal toxicity, the incidence of some skeletal defects was significantly increased after exposure to caffeine, aspirin, or maternal restraint, and their binary and ternary combinations. CONCLUSIONS: Although caffeine and aspirin were given in a single dose in this study, the results suggest that prenatal stress could slightly exacerbate the maternal and developmental toxicity of the combination of these drugs in mice.     

Developmental Toxicity Studies with Atrazine and its Major Metabolites in Rats and Rabbits

Atrazine (ATR), hydroxyatrazine (OH‐ATR), and the three chloro metabolites of ATR (deethylatrazine [DEA], deisopropylatrazine [DIA], diaminochlorotriazine [DACT]) were evaluated for developmental effects in rats and rabbits. Three developmental toxicity studies were conducted on ATR in rats (two studies) and rabbits and a developmental toxicity study was conducted in rats for each of the four ATR metabolites DEA, DIA, DACT, and OH‐ATZ. ATR administration by gavage to pregnant rats and rabbits from implantation (gestation day [GD] 6 in rat, GD 7 in rabbit) through closure of the palate (GD 15 in rat and GD 19 in rabbit) did not statistically significantly alter the incidence of developmental abnormalities or malformations at dose levels up to 100 (rat) or 75 (rabbit) mg/kg bw/day. There were no effects on developmental toxicity parameters for DEA, DIA, DACT, or OH‐ATR at oral dose levels up to 100, 100, 150, or 125 mg/kg bw/day, respectively, with the exception of reductions in fetal body weight by DACT and OH‐ATR in the presence of decreased maternal body weight gain. ATR did not adversely affect developmental end points in a two‐generation study conducted in rats exposed to dose levels up to 500 ppm (38.7 mg/kg/day) in the diet. The 500‐ppm dose level resulted in significantly reduced maternal body weight gain. Overall, data show that neither ATR nor its metabolites statistically significantly affected rat or rabbit embryo‐fetal development even at dose levels producing maternal toxicity.     

Different embryo-fetal toxicity effects for three VLA-4 antagonists

BACKGROUND: VLA‐4 (Very late antigen 4, integrin α₄β₁) plays an important role in cell‐cell interactions that are critical for development. Homozygous null knockouts of the α₄subunit of VLA‐4 or VCAM‐1 (cell surface ligand to VLA‐4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA‐4 antagonists. METHODS: IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo‐fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally. RESULTS: IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo‐fetal effects consisted of slightly lower body weight and crown‐rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo‐fetal effects consisted of increased total post‐implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses. CONCLUSIONS: Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo‐fetal effects at maternally‐toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species. Birth Defects Res B 71:55–68, 2004. © 2004 Wiley‐Liss, Inc.     

Evaluation of developmental toxicity induced by anticholinesterase insecticide,diazinon in female rats

Developmental toxicities, including birth defects, are significant public health problems. This study was planned to assess the cholinergic and developmental potentials of diazinon that is widely used as an organophosphate insecticide. Pregnant female Sprague‐Dawley rats were given diazinon orally at doses of 0, 1.9, 3.8, and 7.6 mg/kg body weight (b.w.)/day on gestation days 6 to 15. Maternal brain acetylcholinesterase activities, measured on gestation day20, were significantly decreased at 3.8 and 7.6 mg/kg b.w./day, but fetal acetylcholinesterase activity was not altered. Maternal toxicities, as evidenced by cholinergic symptoms including diarrhea, tremors, weakness, salivation, and decreased activities, were observed at the 3.8 and 7.6 mg/kg b.w./day dose groups. Net gravid uterine weight was decreased at a dose of 7.6 mg/kg b.w./day. No maternal effects were apparent in the 1.9 mg/kg b.w./day dose group. Maternal toxicity at a dose of 3.8 mg/kg b.w./day did not induce fetotoxicity or teratogeneicity. However, 7.6 mg/kg b.w./day doses significantly resulted in fetal toxicity and malformations in addition to maternal toxicity in animals. In conclusion, teratogenic disorders only outlined by doses that produced marked maternal toxicity. Since the malformations were not morphologically related, they were considered to be secondary to maternal toxicity; hence, the malformations were not related to cholinesterase inhibition. Birth Defects Res (Part B) 92:534–542, 2011. © 2011 Wiley Periodicals, Inc.     

Developmental toxicity evaluation of orthovanadate in the mouse

Sodium orthovanadate in deionized water was administered once daily by gavage on gestational days 6-15 to mice at doses of 0, 7.5, 15, 30, and 60 mg/kg. Dams were killed on day 18 of pregnancy, and fetuses were examined for external, visceral, and skeletal defects. Maternal toxicity was observed at the highest doses of sodium orthovanadate, as evidenced by a significant number of deaths (60 and 30 mg/kg/d) and reduced weight gain and food consumption (30 and 15 mg/kg/d). Embryolethality and teratogenicity were not observed at maternally toxic doses and below, but fetal toxicity was evidenced by a significant delay in the ossification process of some skeletal districts at 30 mg/kg/d. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 7.5 mg/kg/d, and 15 mg/kg/d represented a NOAEL for developmental toxicity in mice under the conditions of this study.     

Developmental toxicity of carbon black oil in mice

BACKGROUND: Carbon black oil (CBO) is a refinery side-stream product used to produce asphalt and other commercial products. CBO contains several classes of hydrocarbons, several of which are known to exhibit systemic and gestational toxicities, making this mixture a candidate for causing reproductive toxicity. METHODS: Swiss-Webster mice were administered CBO (300, 350, 400 mg/kg/day) via oral gavage in a dosage volume of 10 microl/g body weight on gestation days (GD) 6-15. Uterine contents were evaluated on GD 18. RESULTS: Treatment with CBO at all dosage levels resulted in a high frequency of maternal clinical symptoms and a decrease in maternal weight gain. Decreased fetal viability was observed, manifested as a decrease in viable implants and, in a high percentage of treated dams, as early resorption of the entire litter. A significant reduction in fetal weight was also observed. However, neither structural malformations nor developmental delays in ossification were observed in any of the living offspring. To minimize maternal toxicity, the dosage range was lowered (100, 200, 300 mg/kg/day), and the concentration was adjusted such that the volume administered to each dam was decreased by 20%. In this trial, the only maternal effect observed was an increase in maternal liver weight at 200 and 300 mg/kg. The fetal lethality effects observed previously were reduced substantially. Nevertheless, the frequency of resorption among all treatment groups was higher statistically than in controls. CONCLUSIONS: These data support the hypothesis that CBO is reproductively toxic in Swiss-Webster mice at oral doses of >/=100 mg/kg/day.