Many antiepileptic drugs (AEDs) have therapeutic applications that extend beyond epilepsy to include neuropathic pain, migraine headaches and psychiatric disorders. The risk of some AEDs has been clearly established, but for newer drugs, small sample sizes and polytherapy exposures preclude a conclusive determination of their teratogenic potential. Most women with epilepsy will require AED therapy throughout their entire pregnancy to control seizures; the vast majority of pregnancies in women with epilepsy have positive outcomes. A conservative estimate suggests that AED monotherapy doubles, and polytherapy triples, the risk for major congenital malformations. Furthermore, while evidence is still accruing, recent investigations suggest that exposure to select AEDs results in altered cognitive function later in development. There is no evidence to suggest that additional folic acid supplementation ameliorates the increased risk of congenital malformations conferred by in utero AED exposure.

Teratogenic effects of antiepileptic drugs.

The effect of quinalphos (O-O-diethyl-O-[quinoxalinyl-(2)-thionophosphate]), an environmental oestrogenic organophosphorus insecticide pollutant, was studied on Sprague-Dawley albino rats at doses of 250 and 500 microgram kg(-1) body wt. i.p. for 3, 8 and 15 days, respectively. After the treatment with quinalphos there was an increase in the lipid peroxides (as measured by manoldialdehyde production) and a decrease in the total lipid content for the testicular membrane. The effects were more pronounced at the low doses than at the higher doses, indicating that some physiological defence mechanisms were in operation at higher doses. The free-radical-scavenging enzymes (superoxide dismutase, catalase and glutathione peroxidase) showed significantly higher activity at high dose in comparison to their activities at low-dose treatment. Glutathione content was gradually reduced after quinalphos treatment, both in low and high doses. Histomorphohological studies showed that after the low-dose treatment shrinkage of the tubular diameter and testicular atrophy leading to degenerative changes in the germinal epithelium were observed. But at high dose, gradual recovery of various germ cell layers and significant expansion of seminiferous tubules of Sprague-Dawley rat testes were found; the latter is generally believed to be a useful index of testicular activity through the hypothalamo-hypophyseal-gonadal axis. The present study indicates that quinalphos caused damage and degeneration of the testicular tissues due to free-radical-mediated lipid peroxidation at low doses. We have also demonstrated that, in response to the damage, an endogenous antioxidant enzyme defence system became operative at the higher dose of treatment.

Study of quinalphos (an environmental oestrogenic insecticide) formulation (Ekalux 25 E.C.)-induced damage of the testicular tissues and antioxidant defence systems in Sprague-Dawley albino rats.

Early life stress in epilepsy: A seizure precipitant and risk factor for epileptogenesis

Tracheal agenesis is a rare malformation of the lower respiratory tract. Investigation of a patient with multiple congenital anomalies and tracheal agenesis prompted a review of the literature which uncovered 42 previously published cases, most of whom had other defects. The presence in our patient of a tracheal abnormality in association with radial hypoplasia, single umbilical artery, tetralogy of Fallot, and left hydroureter initially suggested presence of the VACTERL association. However, numerical classification of malformation patterns in the reported patients with tracheal agenesis and in a series of patients with tracheoesophageal fistula and other components of the VACTERL association suggests that tracheal agenesis does not occur in the VACTERL association and may be part of another pattern of malformations which includes laryngeal atresia, complex congenital heart anomalies, radial ray defects, and duodenal atresia.

Tracheal agenesis and associated malformations : a comparison with tracheoesophageal fistula and the VACTERL association

Early-life stress includes prenatal, postnatal, and adolescence stress. Early-life stress can affect the development of the hypothalamic-pituitary-adrenal (HPA) axis, and cause cellular and molecular changes in the developing hippocampus that can result in neurobehavioral changes later in life. Epidemiological data implicate stress as a cause of seizures in both children and adults. Emerging evidence indicates that both prenatal and postnatal stress can prime the developing brain for seizures and an increase in epileptogenesis. This article reviews the cellular and molecular changes encountered during prenatal and postnatal stress, and assesses the possible link between these changes and increases in seizure occurrence and epileptogenesis in the developing hippocampus. In addititon, the priming effect of prenatal and postnatal stress for seizures and epileptogenesis is discussed. Finally, the roles of epigenetic modifications in hippocampus and HPA axis programming, early-life stress, and epilepsy are discussed.

/pdf/early-life-stress-impacts-the-developing-hippocampus-and-vmet5oj2qs.pdf

Early-life stress impacts the developing hippocampus and primes seizure occurrence: cellular, molecular, and epigenetic mechanisms

A group of 88 spontaneously occurring variations of the skeleton were studied in adult CD-1 mice which had been exposed in utero to the herbicides 2,4,5-T or Trifluralin, administered to their dams by gavage, in an attempt to detect subtle biological effects of these compounds even in the absence of gross malformations. Sixty-seven characters showed variation in this population. Of these, 19 were significantly different in frequency from untreated controls in mice having received a teratogenic dose of 2,4,5-T, with an average difference of 23.7%. Seventeen of them were increased in frequency. By contrast, only three traits differed from untreated among mice receiving a no-effect dose of 2,4,5-T. Twelve traits differed significantly from untreated in the Trifluralin-treated group; the average difference was 18.8%, with 10 of the traits being increased in frequency.



Two clusters of affected variants specific to the 2,4,5-T high dose group included frontal bone variants in the skull (presence of an interfrontal bone and fusion of the frontals) and variants in the cervical vertebrae (imperfect foramina in the first and second cervicals, dyssymphysis of the second cervical, and a shift of the arch foramen from the fourth to the fifth cervical). Two other effects peculiar to the 2,4,5-T-treated specimens were a loss of the prominent dorsal spine of the second thoracic vertebra and a reduction in the number of caudal vertebrae. The most obvious effects specific to the Trifluralin treatment were an increase in occurence of 14 ribs, an undoubled foramen ovale, and the occurence of accessory foramina in the cervical vertebrae. A striking increase in frequency of parted frontals was seen in both 2,4,5-T high dose and Trifluralin-treated groups.



The skeletal variant assay system may be useful as a postnatal screen for detecting prenatal exposure to potentially noxious substances.

Assessment of adult skeletons to detect prenatal exposure to 2,4,5-T or Trifluralin in mice.

A skeletal variant assay system (SVAS) consisting of a group of 88 spontaneously occurring qualitative variations of the adult mouse skeleton was applied to CD-1 animals that had been exposed in utero to 0, 200, or 1,000 mg/kg/day of the sodium salt of acetazolamide dissolved in distilled water, presented by SC injection of the dam during day 8 or days 9-11 of gestation. Two separate series of experiments were performed, and skeletons were examined at postnatal 62 +/- 2 days. Variation occurred in 62 and 67 characters in the two series. Frequencies of occurrence differed from untreated (UNTD) and vehicle-treated (VEH) values of substantial numbers of variants in a dose related manner for both series in both treatment regimes as did the number of variants which showed significantly different frequencies (P less than .01) in comparisons of experimental with either UNTD or VEH. At the high doses 12 and 16 variants occurred with significantly different frequencies from UNTD in day 8 treatments in the two series, and 15 and 19 variants differed in the days 9-11 treated group. Contrasting high-dose animals with appropriate vehicle controls revealed differences in 13 and 12 variants in day 8 treatment groups and in 18 and 15 variants in days 9-11 groups. Agreement between the two series was good, especially in the D9-11 treatments. Several variants differed significantly from both UNTD and VEH in both series of experiments. Among these were a number which appeared more or less specific to acetazolamide exposure. They include: day 8 treatments--accessory parietal, frontal extension, and 27 presacral vertebrae; day 9-11 treatments--sacral fusions in dorsal processes and vertebral bodies, and caudal fusions and malformations; both sets of treatments--lumbar fusions, and fusions of the transverse processes of the sacral vertebrae. Other importantly affected variants, also seen in exposure to other compounds include: day 8 treatments--abnormal metoptic roots; day 9-11 treatments--accessory mental foramen, foramina transversaria imperfecta of the atlas, arch foramen of the fifth cervical (C) vertebra, malformed sternebrae, fossa olecrani perforata, and fewer than 30 caudal vertebrae; both treatment regimes--parted frontals, accessory transverse foramina in C3-C6, reduced articular processes on the thoracic vertebrae, and 14 ribs. By all criteria applied, the SVAS is able to detect prenatal exposure to acetazolamide in adult skeletons even in the absence of any gross morphological abnormalities.

Assessment of adult skeletons to detect prenatal exposure to acetazolamide in mice

Fetal mice treated on days 10, 11, and 12 of gestation by injecting the mothers with (i) 50 milligrams of beta-2-thienylalanine, (ii) solvent, or (iii) sham injection had identical frequencies of audiogenic seizures when tested 23 days after birth; these frequencies were significantly higher than those of an unhandled control group. Results of the sham treatment suggest that maternal stress induced by handling, rather than the nature of the substance injected, increased the susceptibility of the offspring to seizures.

Suceptibility of mice to audiogenic seizures is increased by handling their dams during gestation

Subcutaneous injection of pregnant mice on day 8 of gestation with 1,000 mg/kg or 200 mg/kg of an aqueous solution of the sodium salt of acetazolamide, divided into three equal treatments at 8-hour intervals, in two series of experiments performed 8 months apart on separately purchased random bred CD-1 animals, resulted in the occurrence of a novel variant of the frontal bones of the skull when animals exposed in utero were examined at 62 ± 2 days postnatal.



In its greatest manifestation this variation consisted of a 2–3 mm posteriad extension of the dorsomedial portion of the posterior margin of both bones, although all degrees of asymmetry and variations in the extent of involvement of the posterior margin of the bones were seen. This frontal extension variant was seen in 30.9 ± 4.7% and 53.1 ± 5.0% of the 97 and 98 specimens in the highdose groups, and in 8.1 ± 2.7% and 14.6 ± 3.7% of the 99 and 89 low-dose specimens in the two series. It was not seen in untreated groups, or to any significant extent in vehicle-treated groups, or in a treatment regime involving exposure during days 9–11 of gestation. It was also not seen in 2,110 specimens from four other series of experiments reported in detail involving the teratogens, trypan blue (two series), 5-bromodeoxyuridine, or 2,4,5-T, or in approximately 1,000 specimens from comparable experiments with a variety of pesticides (Maneb, Captan, Trifluralin, Decamethrin) or Thalidomide.



In contrast, a morphologically analogous variant, accessory parietal, in which a suture in the anterodorsal surface of the parietal bones running posteromedial and seemingly delimiting a separate bone, is seen in all series. Although it looks as though frontal extension could be an accessory parietal fused with the frontal bone, observation of the specimens does not strongly support that relationship. Even if that were the case, it happens only in day-8 acetazolamide exposure.



From the rather extensive series of observations performed, it would appear that frontal extension is a specific response to in utero exposure to acetazolamide during the day 8 of gestation.

Another specific effect of prenatal acetazolamide exposure in the mouse.

A four-way cross mouse population was established and four successive generations of animals were treated with trypan blue, selection being applied for susceptibility and resistance to the teratogen. The selection was successful, 26.8 ± 1.7% of all animals in the susceptible line (CBHA-S) being abnormal and only 8.6 ± 1.7% of resistant (CBHA-R) individuals being affected by the treatment. An unselected control line (CBHA-C) produced an intermediate frequency of abnormality when treated. The vast majority of the abnormalities produced were of the tail and involved kinking, shortening, vertebral fusions and the occurrence of a completely novel malformation—an accessory tail. Both the proportion of litters affected by the treatment and the proportion of abnormal individuals within affected litters differed in the selected lines.

Results of selection for susceptibility and resistance to trypan blue teratogenesis in a four‐way outcross mouse population

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