Maternal Hepatotoxicity Research Articles

Adverse effects of gestational exposure to hexafluoropropylene oxide trimer acid (HFPO-TA) homologs on maternal, fetal, and placental health in mice

In an effort to identify and develop potential alternatives for perfluorooctanoic acid (PFOA), PFDMO2HpA and PFDMO2OA have been engineered by reducing the -CF2 content in the molecular structure of hexafluoropropylene oxide trimer acid (HFPO-TA). Yet, despite their subsequent presence in environmental samples, there is a paucity of information regarding their toxicity, particularly on pregnancy. Here, pregnant CD-1 mice were exposed to PFDMO2HpA (0, 0.04, 0.16, 0.63, 2.5, or 10 mg/kg/day) or PFDMO2OA (0, 0.01, 0.04, 0.16, 0.63, or 2.5 mg/kg/day) via oral gavage from gestational days 2 (GD2) to 12 or 18 to evaluate the detrimental effects on dams and embryo-placenta units. Both two chemicals can transfer across the placenta, with a higher transfer ratio in late-pregnancy (GD18) than in mid-pregnancy (GD12), and PFDMO2OA being transferred at a higher rate than PFDMO2HpA. PFDMO2HpA/PFDMO2OA exposure caused maternal hepatotoxicity and fetal hepatomegaly, showing the lowest no-observed-adverse-effect level among all observed endpoints, which were used for calculating their reference dose (13.33 ng/kg/day). In the 2.5 and 10 mg/kg/day PFDMO2HpA groups as well as 2.5 mg/kg/day PFDMO2OA group at GD18, besides the abnormally high abortion rates exceeding 5 %, survival fetal weight was notably reduced (2.33 %, 6.44 %, and 5.59 % decrease relative to corresponding controls, respectively). Concurrently, placentas exhibited significant enlargement following PFDMO2HpA or PFDMO2OA exposure at doses of 0.63 mg/kg/day or higher, resulting in diminished placental efficiency. The deleterious effects of two chemicals on dams, fetuses, and placentas were stronger than that of PFOA or HFPO-DA, suggesting that neither PFDMO2HpA nor PFDMO2OA is suitable PFOA alternative. Bioinformatics analyses revealed significant alterations in the expression of genes involved in inflammation and immunity in the placenta upon exposure to 10 mg/kg/day PFDMO2HpA and 2.5 mg/kg/day PFDMO2OA at GD18, potentially elucidating mechanism behind the observed decrease in placental efficiency and increase in abortion rates after exposure.

Toxicological effects of the Morinda citrifolia L. fruit extract on maternal reproduction and fetal development in rats

Morinda citrifolia L., also known as Noni, is widely used plant in folk medicine for various therapeutic purposes. However, reports on its effects during pregnancy are limited. Therefore, the objective of this study was to evaluate the effects of the M. citrifolia fruit extract on maternal performance and fetal development during pregnancy in rats. Pregnant Wistar rats (n = 12/group) were treated from gestational days (GD) 0–21 with water (control group) or the aqueous extract of M. citrifolia fruit at doses of 200, 400, or 750 mg/kg, orally. During pregnancy, clinical signs of toxicity, maternal weight, feed intake, and water consumption were noted. On GD 21, the rats were anesthetized and blood was collected to evaluate various biochemical parameters. During laparotomy, reproductive performance parameters were recorded, and fetuses were weighed and the anomalies analyzed. Reduced placental efficiency and fetal growth restriction were observed in the group treated with 400 mg/kg of M. citrifolia extract. The highest dose (750 mg/kg) augmented aspartate aminotransferase concentration and preimplantation losses, while reducing the number of live fetuses. Furthermore, both doses (400 and 750 mg/kg) of the plant extract caused fetal anomalies. In conclusion, consumption of high doses of the M. citrifolia aqueous extrac during pregnancy leads to maternal hepatotoxicity, anti-implantation effects, intrauterine growth restriction and fetal abnormalities, indicating that the plant fruit extract can be harmful to both the mother and the fetus.

Gestational exposure to GenX induces hepatic alterations by the gut-liver axis in maternal mice: A similar mechanism as PFOA

GenX is an alternative to perfluorooctanoic acid (PFOA) and was included in the accession list of Substances of Very High Concern in 2019. Gestational GenX exposure induces maternal hepatotoxicity in animals. However, the mechanisms of GenX toxicity have not been explored. In the present study, pregnant Balb/c mice were administered with PFOA (1 mg/kg BW/day), GenX (2 mg/kg BW/day), or Milli-Q water by gavage during gestation. Similar hepatic pathological changes, including enlargement of hepatocytes, cytoplasm loss, nucleus migration, inflammatory cell infiltration, and reduction of glycogen storage, were observed in PFOA and GenX groups. Increased expression levels of indicators of the TLR4 pathway indicated activation of inflammation in the liver of maternal mice after exposure to PFOA or GenX, consistent with the pathological changes. Overexpression of cleaved PARP-1, cleaved caspase 3, Bax and decreased Bcl-2 proteins indicated activation of apoptosis, whereas overexpression of ULK-1, p62, beclin-1, LC3-II proteins and downregulation of p-mTOR implied that PFOA and GenX exposure initiated autophagy. Decreased secretion of mucus, reduced expression levels of tight junction proteins, and higher serum levels of lipopolysaccharide indicated disruption of the intestinal barrier. Translocation of lipopolysaccharide may be recognized by TLR4, thus triggering inflammatory pathway in the maternal liver. In summary, gestational exposure to PFOA or GenX induced maternal hepatic alterations through the gut-liver axis.

Prophylaxis for Tuberculosis in Pregnant Women.

As more women at increased risk for tuberculosis (TB) reactivation immigrate to the United States, perinatal screening and chemoprophylaxis are increasingly important. Interferon-gamma release assays and the tuberculin skin test are acceptable screening tests with the latter supported by more data in pregnancy. Women screening positive should have active TB excluded, and if negative, latent TB is likely. Prophylaxis should be deferred until 3 months postpartum except in those severely immunosuppressed, human immunodeficiency virus positive, or recently exposed. Isoniazid with pyridoxine for 9 months is preferred with reasonable safety in pregnancy and breastfeeding. Monitoring for maternal hepatotoxicity is recommended.

Liver Profile of Atazanavir/Ritonavir in Pregnant Albino Rats

Medication use during pregnancy is challenging due to the occurrence of maternal or fetal toxicities. Atazanavir/ritonavir (ATV/r) has hepatotoxic potential hence; use in pregnant patients living with human immunodeficiency virus may cause maternal hepatotoxicity. This study assessed the liver profile of ATV/r in pregnant albino rats. Thirty pregnant albino rats randomized into groups were orally treated daily with ATV/r (4.28/1.43 mg/kg-34.3/11.4 mg/kg) for 16 days. After treatment, the rats were weighed and sacrificed. Blood samples were collected and examined for serum biochemical parameters. Liver samples were weighed and assessed for biochemical and histological changes. Body and liver weights were normal (p>0.05) in ATV/r-treated pregnant rats when compared to control. Serum total cholesterol, triglyceride, low density lipoprotein cholesterol and blood glucose levels were significantly (p<0.01) elevated whereas high density lipoprotein cholesterol level was significantly (p<0.01) decreased in rats treated with ATV/r (34.3/11.4 mg/kg) when compared to control. Liver and serum aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, total bilirubin, and conjugated bilirubin levels were significantly increased in a dose-dependent fashion in rats treated with ATV/r; 8.57/2.86 mg/kg (p<0.05), 17.1/5.72 mg/kg (p<0.01) and 34.3/11.4 mg/kg (p<0.001) when compared to control. Liver superoxide dismutase, catalase, glutathione and glutathione peroxidase levels were significantly decreased whereas malondialdehyde levels were significantly increased in a dose-dependent fashion in rats treated with ATV/r; 8.57/2.86 mg/kg (p<0.05), 17.1/5.72 mg/kg (p<0.01) and 34.3/11.4 mg/kg (p<0.001) when compared to control. Necrotic hepatocytes were observed at higher doses of ATV/r. ATV/r may not be hepatotoxic in pregnant women living with HIV at the clinical dose.

Deoxynivalenol-induced oxidative stress and Nrf2 translocation in maternal liver on gestation day 12.5 d and 18.5 d

Deoxynivalenol (DON) contamination is indicated as a worldwide problem since it causes economic losses for the grain and is a potential threat to both animal and human health. This study concentrated on DON-induced oxidative damage and the accompanying nuclear factor erythroid 2-related factor 2 (Nrf2) translocation during DON-induced maternal hepatotoxicity. The 0, 1.0 and 2.5 mg/kg/day of DON were used as doses for the experiment during gestation days. DON slightly increased the levels of ALT and AST in GD12.5 d instead of GD18.5 d. Oxidative stress and anti-oxidization system were both found to be activated in the experiment which marked by ROS, MDA and GSH increasing, especially on GD12.5 d. The levels of HO-1 were significantly increased by DON exposure at different two time points. Moreover, Nrf2 translocation appeared both in GD 12.5 d and GD 18.5 d. In conclusion, DON-induced ROS accumulation may cause maternal liver damage in the initial stages, but the related stimulation of Nrf2/HO-1 pathway improves the removal of ROS and decreases the level of oxidative stress thereby protecting the liver damage. Therefore, upregulating the Nrf2-dependent response is one of the potential methods that protects maternal liver from DON-induced oxidative damage.

Acetaminophen Overdose in a Third Trimester Pregnancy

SESSION TITLE: Poisoning and Drug Overdose 1 SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Acetaminophen (APAP) toxicity is commonly reported and it is a major cause of drug induced acute liver failure. Toxicity during the third trimester of pregnancy can result in maternal and fetal hepatotoxicity, premature labor and fetal death. We present a case of APAP overdose in a pregnant patient in her third trimester, who despite a high APAP level and premature rupture of membranes, did not develop hepatotoxicity and did not require an emergent delivery CASE PRESENTATION: A 24 year old female, 31 weeks pregnant, was brought to the ED after she was found unresponsive with bottles of clonazepam 0.5 mg and APAP 500 mg. She presented with CNS depression requiring intubation and admission to the Medical intensive Care Unit where she was found to have premature rupture of membranes with no evidence of fetal distress. Ultrasound confirmed gestational age and normal fetal anatomy. The 4 hour APAP level was 344 mcg/ml and IV N-acetylcysteine (NAC) 21 hour protocol was administered. Initial ALT /AST 14 /24 U/L, INR 0.99. APAP levels decreased to < 10 mcg/ml within 24 hours with no elevation of ALT/ AST at 48 hours. Urine drug screen was positive for cannabinoids, benzodiazepines, tricyclic antidepressants. 20 hours after presentation, the patient was extubated and transferred to the OB service. At 34 weeks gestation she had a C section delivery of an infant that required a short NICU stay DISCUSSION: The fetal liver is susceptible to APAP-induced injury because it is capable of oxidative metabolism which produces the toxic metabolite “NAPQI”, and the fetus has limited glutathione stores. CYP 450 activity is detected in fetal livers at 18 weeks gestation. The optimal efficacy of NAC is within 8 hours of a toxic APAP ingestion. Delayed administration increases the risk of hepatotoxicity. In pregnancy, treatment with IV NAC is preferred over oral formulations in order to achieve high maternal and fetal bioavailability. Published case series of pregnant women in their third trimester with toxic APAP levels suggest that the majority recover and deliver full term babies. However, premature delivery, stillbirths, and neonatal death have been reported with increased risk in the setting of maternal hepatotoxicity. Severe maternal hepatotoxicity associated with signs of fetal distress is an indication for urgent delivery CONCLUSIONS: Pregnant women with acute APAP overdose should be treated early with IV NAC. Delayed therapy is associated with maternal and fetal hepatotoxicity. Overdose, in the presence or abscence of hepatotoxicity, may precipitate premature labor and fetal death. Successful treatment of APAP overdose during pregnancy requires supportive care, early administration of IV NAC and a multidisciplinary team of specialists (intensivists, toxicologists, obstetricians and neonatologists) to optimize maternal-fetal outcome Reference #1: Goldfrank’s Toxicological Emergencies,10th edition, 2015, McGraw-Hill, New York; Chapter 31: Reproductive and Perinatal Principles DISCLOSURE: The following authors have nothing to disclose: George Samuel, Lydia Baltarowich, Kamelia Albujoq, Said Chaaban, Muhammad Usman, Daniel Ouellette No Product/Research Disclosure Information

Rodent Thyroid, Liver, and Fetal Testis Toxicity of the Monoester Metabolite of Bis-(2-ethylhexyl) Tetrabromophthalate (TBPH), a Novel Brominated Flame Retardant Present in Indoor Dust

Background: Bis-(2-ethylhexyl) tetrabromophthalate (TBPH) is widely used as a replacement for polybrominated diphenyl ethers (PBDEs) in commercial flame retardant mixtures such as Firemaster 550. It is also used in a commercial mixture called DP 45. Mono-(2-ethyhexyl) tetrabromophthalate (TBMEHP) is a potentially toxic metabolite.Objectives: We used in vitro and rodent in vivo models to evaluate human exposure and the potential metabolism and toxicity of TBPH.Methods: Dust collected from homes, offices, and cars was measured for TBPH by gas chromatography followed by mass spectrometry. Pregnant rats were gavaged with TBMEHP (200 or 500 mg/kg) or corn oil on gestational days 18 and 19, and dams and fetuses were evaluated histologically for toxicity. We also assessed TBMEHP for deiodinase inhibition using rat liver microsomes and for peroxisome proliferator-activated receptor (PPAR) α and γ activation using murine FAO cells and NIH 3T3 L1 cells.Results: TBPH concentrations in dust from office buildings (median, 410 ng/g) were higher than in main living areas in homes (median, 150 ng/g). TBPH was metabolized by purified porcine esterases to TBMEHP. Two days of TBMEHP exposure in the rat produced maternal hypothyroidism with markedly decreased serum T3 (3,3´,5-triiodo-l-thyronine), maternal hepatotoxicity, and increased multinucleated germ cells (MNGs) in fetal testes without antiandrogenic effects. In vitro, TBMEHP inhibited deiodinase activity, induced adipocyte differentiation in NIH 3T3 L1 cells, and activated PPARα- and PPARγ-mediated gene transcription in NIH 3T3 L1 cells and FAO cells, respectively.Conclusions: TBPH a) is present in dust from indoor environments (implying human exposure) and b) can be metabolized by porcine esterases to TBMEHP, which c) elicited maternal thyrotoxic and hepatotoxic effects and d) induced MNGs in the fetal testes in a rat model. In mouse NIH 3T3 L1 preadipocyte cells, TBMEHP inhibited rat hepatic microsome deiodinase activity and was an agonist for PPARs in murine FAO and NIH 3T3 L1 cells.

A Safety Assessment of the Antimalarial Herb Artemisia annua During Pregnancy in Wistar Rats

Artemisia annua is a Chinese antimalarial herb that has been used for more than 2000 years. The maternal and foetal safety of the ethanolic leaf extract of therapeutically active Artemisia annua (EAA), with previously determined artemisinin yield of 1.098% was evaluated in Wistar rats. Twenty pregnant rats, divided into four study groups of saline treated (control), and test groups administered orally with 100, 200 and 300 mg/kg body weights of EAA, respectively, from gestation days (GD) 8 to 19. Following overnight fast, animals were sacrificed on GD 20, and maternal blood was collected to evaluate biochemical and haematological markers. Foetuses were carefully removed, weighed, and observed for any possible malformation. Biochemical and haematological studies revealed that EAA did not result in maternal hepatotoxicity, haematotoxicity, and hyperlipidemia. While litter size significantly decreased (p < 0.05) at 100 mg/kg EAA, maternal estrogen levels decreased in all the EAA-treated groups. Non-viable (21%) and malformed (31%) foetuses were observed at the 300 mg/kg dose of EAA, which implies that although consumption of the leaf extract may not predispose users to hepatotoxicity, haematotoxicity, and hyperlipidemia, it should be taken with caution during pregnancy due to possible risk of embryotoxicity at concentrations higher than the therapeutic dose.

Effects of oral administration of crude leaf extracts of Aglaia loheri Blanco and Ardisia pyramidalis (Cav.) Pers on mouse embryo morphology and maternal reproductive performance

Aglaia loheri Blanco and Ardisia pyramidalis (Cav.) Pers are both endemic plant species with a variety of bioactive compounds, but remain largely untested for their toxicity, and their effects on maternal reproductive performance and fetal morphology. Inbred ICR mice were orally administered with 10 and 5 mg/ml concentrations for A. loheri, and 10 and 1 mg/ml concentrations for A. pyramidalis from the 8th to the 15th day of pregnancy. Dissection at 16 days post coitum (dpc) showed significant differences in maternal reproductive performance, as estimated by gestation index, % dead implants, % females with resorption, % resorption and % fetus with morphological abnormalities. For A. pyramidalis, the 1 mg/ml extract + vitamin A treatment reduced maternal reproductive performance most significantly, while, for A. loheri, treatment with 10 mg/ml extract, with or without vitamin A, as well as with 5 mg/ml extract only resulted to a 100% resorption. Additionally, maternal hepatotoxicity was observed in mice treated with A. pyramidalis, while significant weight losses among mice treated with higher doses of A. loheri + vitamin A suggests toxicity and synergism with vitamin A. These results suggest that caution must be taken when taking these extracts during pregnancy due to their possible toxicity and teratogenicity. Key words: Aglaia loheri Blanco, Ardisia pyramidalis (Cav.) Pers, Meliaceae, Myrsinaceae, teratogenicity, hypervitaminosis A, reproductive performance, embryo morphology.

Management of hyperthyroidism during pregnancy and lactation

Poorly treated or untreated maternal overt hyperthyroidism may affect pregnancy outcome. Fetal and neonatal hypo- or hyper-thyroidism and neonatal central hypothyroidism may complicate health issues during intrauterine and neonatal periods. To review articles related to appropriate management of hyperthyroidism during pregnancy and lactation. A literature review was performed using MEDLINE with the terms 'hyperthyroidism and pregnancy', 'antithyroid drugs and pregnancy', 'radioiodine and pregnancy', 'hyperthyroidism and lactation', and 'antithyroid drugs and lactation', both separately and in conjunction with the terms 'fetus' and 'maternal.' Antithyroid drugs are the main therapy for maternal hyperthyroidism. Both methimazole (MMI) and propylthiouracil (PTU) may be used during pregnancy; however, PTU is preferred in the first trimester and should be replaced by MMI after this trimester. Choanal and esophageal atresia of fetus in MMI-treated and maternal hepatotoxicity in PTU-treated pregnancies are of utmost concern. Maintaining free thyroxine concentration in the upper one-third of each trimester-specific reference interval denotes success of therapy. MMI is the mainstay of the treatment of post partum hyperthyroidism, in particular during lactation. Management of hyperthyroidism during pregnancy and lactation requires special considerations and should be carefully implemented to avoid any adverse effects on the mother, fetus, and neonate.

Maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy

To describe the maternal tolerability of nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland and to determine risk factors for development of significant hepatotoxicity. A retrospective study was carried out of all women prescribed nevirapine as part of combination antiretroviral therapy in pregnancy at three HIV centres in Dublin, Ireland (October 2000 to February 2003). Toxicities experienced were graded according to the Division of AIDS toxicity guidelines for adults. Statistical analysis was performed to determine whether there were differences between those that did and those that did not experience significant hepatotoxicity. A total of 123 women initiated nevirapine as part of combination antiretroviral therapy in the study period. Eight women developed significant hepatotoxicity, including two women who died from fulminant hepatitis. Women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts (P=0.01). In this cohort, women who experienced more severe hepatotoxicity had higher pretreatment CD4 counts, lending additional weight to the need for caution in using nevirapine as part of combination antiretroviral therapy in women not requiring antiretroviral therapy for their own health.

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 GD18. 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.

Developmental effects of fumonisin B1-containing Fusarium moniliforme culture extract in CD1 mice.

Pregnant Charles River CD1 mice were treated with a semipurified extract of Fusarium moniliforme culture containing 0, 12.5, 25, 50 or 100 mg FB1/kg each day orally (diluted in distilled water) between gestational days (GD) 7 and 15 to evaluate the developmental toxicity of FB1. Following sacrifice of dams on GD 18, litters were examined for gross abnormalities and divided equally for skeletal or visceral examination by routine techniques. Significant maternal mortality was observed at doses of 50 and 100 mg FB1/kg. Dose-dependent decreases in maternal body weight gains, number of live offsprings per litter, and mean body weight of the offspring were produced at FB1 doses of 25 mg/kg or higher. The percentage of implants resorbed increased at all doses in a dose-dependant manner. A dose-dependant increase, except at the lowest dose tested, in the incidence of ossification deficits involving digits and sternum, short and wavy ribs, and hydrocephalus of lateral and third ventricles was also evident. Cleft palate was seen only at the highest FB1 dose. Maternal intoxication manifested as a dose-dependant increase in the severity of ascites associated mainly with increased histopathologic scores reflecting hepatocellular damage at day 18. Concommittant increases in serum alanine amino transferase (ALT) on GD 12, reflecting parenchymal liver cell damage, was also observed at all doses above 12.5 mg of FB1/kg. These results suggest that FB1-containing F. moniliforme culture extract is developmentally toxic in mice, and that this toxicity may be mediated by maternal hepatotoxicity.

Can Acetaminophen Excess Result in Maternal and Fetal Toxicity?

This is the third case reported of maternal acetaminophen overdose during pregnancy. Such overdose may be associated with maternal liver toxicity. Fetal hepatotoxicity may be seen in association with maternal hepatotoxicity. As a result, the infant's blood coagulation times may be prolonged, and intracranial hemorrhage at delivery is a concern. Our case shows such a complication after chronic exposure to acetaminophen.