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PubMed2000

Clonal propagation of primate offspring by embryo splitting.

Primates that are identical in both nuclear and cytoplasmic components have not been produced by current cloning strategies, yet such identicals represent the ideal model for investigations of human diseases. Here, genetically identical nonhuman embryos were produced as twin and larger sets by separation and reaggregation of blastomeres of cleavage-stage embryos. A total of 368 multiples were created by the splitting of 107 rhesus embryos with four pregnancies established after 13 embryo transfers (31% versus 53% in vitro fertilization controls). The birth of Tetra, a healthy female cloned from a quarter of an embryo, proves that this approach can result in live offspring.

Animals↗

PubMed1977

Differential effect of various 6-hydroxydopa treatments on the development of central and peripheral noradrenergic neurons.

6-Hydroxydopamine or 6-hydroxydopa injected systemically into newborn rats produced marked changes in the development of central and peripheral noradrenergic neurons. Noradrenaline concentration was elevated in the brain stem, particularly in the pons, and decreased in the cerebral cortex and the spinal cord while in the cerebellum, the effects were dependent on the mode of administration. The changes produced by 6-hydroxydopa in brain regional noradrenaline were related to the dose injected at birth. Similar modifications in the development of central noradrenergic neurons were found in the offspring of rats which had received 6-hydroxydopa at 16 days of gestation. The involvement of peripheral sympathetic neurons varied with the compound used and the form of its administration. Thus, 6-hydroxydopamine produced a permanent although partial peripheral sympathectomy, an effect which was less evident following multiple injections of 6-hydroxydopa after birth and almost minimal after a single injection. The prenatal administration of 6-hydroxydopa did not alter peripheral sympathetic neurons. It is concluded that with the appropriate treatment schedule, it is possible to lesion selectively the noradrenergic neurons in the central nervous system.

Animals↗

PubMed2000

Occurrence of congenital heart defects in relation to maternal mulitivitamin use.

The purpose of this study was to assess the relation between maternal multivitamin use and risk for cardiac defects in the offspring, using a population-based approach. The Atlanta Birth Defects Case-Control study is a population-based case-control study of infants born between 1968 and 1980 to mothers residing in metropolitan Atlanta, Georgia. The 958 case infants with nonsyndromic cardiac defects were actively ascertained from multiple sources. The 3,029 infants without birth defects (control infants) were selected from birth certificates by stratified random sampling. Periconceptional multivitamin use, defined as reported regular use of multivitamins from 3 months before pregnancy through the first 3 months of pregnancy, was contrasted with no use during the same time period. Periconceptional multivitamin use was associated with a reduced risk for nonsyndromic cardiac defects in the offspring (odds ratio (OR) = 0.76; 95% confidence interval (Cl): 0.60, 0.97). The risk reduction was strongest for outflow tract defects (OR = 0.46; 95% Cl 0.24, 0.86) and ventricular septal defects (OR = 0.61; 95% Cl: 0.38, 0.99). No risk reduction was evident when multivitamin use was begun after the first month of pregnancy. If these associations are causal, the results suggest that approximately one in four major cardiac defects could be prevented by periconceptional multivitamin use.

Adolescent↗

PubMed1989

The clinical relevance of sex selection techniques.

Clinical and laboratory attempts to alter the sex ratio require more complete and thorough study. Improved identification of Y-bearing sperm through chromosome evaluation rather than by F-body identification is critical to provide a more precise definition. The tentative conclusions stated below are based on an assessment of literature from which it is generally difficult to draw conclusions: 1. The timing of intercourse in relation to ovulation and subsequent fertilization appears to influence the sex ratio. More females are conceived when coitus occurs relatively close to ovulation, and more males are conceived when the sperm or egg is in the reproductive tract for a relatively longer time before conception. The influence of coital timing on the sex ratio is overall quite subtle and is not a practical method to alter the sex ratio for individual couples. 2. The use of ovulation-inducing medications slightly favors female offspring. A decrease in sex ratio of 5% to 10% has been shown in multiple studies. 3. Artificial insemination with fresh donor or homologous spermatozoa results in more male births with a reported 7% to 10% increase in the sex ratio. It appears that ovulation induction combined with artificial insemination cancels the respective influences of each on the sex ratio. 4. Sperm separation techniques using albumin (for selection of Y-bearing sperm) or Sephadex column filtration (for selection of X-bearing sperm) are the only techniques that have been reported to alter the sex ratio to a degree that is clinically relevant. Although clinical birth data are just beginning to accumulate, these methods appear to have a 70% to 80% success for selection of assumed Y-bearing sperm and a 75% to 80% success for selection of assumed X-bearing sperm. The validity of these results will remain questionable until fully detailed accounts are published and successfully repeated. Free-flow electrophoresis appears to achieve significant separation; however, the depressed postprocedure spermatozoa motility presently limits the usefulness of this procedure. 5. There is a potential to combine clinical and laboratory methods to maximize the efficiency of sex selection for interested couples. Modern methods to identify ovulation (e.g., urinary LH kits, ultrasonography) may help the timing of coitus for sex selection. Clomiphene citrate may enhance female sex preselection when Sephadex column filtration is also employed. 6. The priority of sex preselection in terms of medical, social, and demographic consideration remains to be determined. The avoidance of sex-linked genetic disorders is a reasonable and desirable goal.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Separation↗

PubMed1999

Maternal pesticide exposure from multiple sources and selected congenital anomalies.

We explored the relation between various potential sources of maternal periconceptional pregnancy exposures to pesticides and congenital anomalies in offspring. Data were derived from a case-control study of fetuses and liveborn infants with orofacial clefts, neural tube defects, conotruncal defects, or limb anomalies, among 1987-1989 California births and fetal deaths. We conducted telephone interviews with mothers of 662 (85% of eligible) orofacial cleft cases, 265 (84%) neural tube defect cases, 207 (87%) conotruncal defect cases, 165 (84%) limb cases, and 734 (78%) nonmalformed controls. The odds ratio (OR) estimates did not indicate increased risk for any of the studied anomaly groups among women whose self-reported occupational tasks were considered by an industrial hygienist likely to involve pesticide exposures. Paternal occupational exposure to pesticides, as reported by the mother, revealed elevated ORs for only two of the cleft phenotypes [OR = 1.7 [95% confidence interval (CI) = 0.9-3.4] for multiple cleft lip with/without cleft palate and OR = 1.6 [95% CI = 0.7-3.4] for multiple cleft palate]. Use of pesticide products for household gardening, by mothers or by professional applicators, was associated with ORs > or =1.5 for most of the studied anomalies. Use of pesticide products for the control of pests in or around homes was not associated with elevated risks for most of the studied anomalies, although women who reported that a professional applied pesticides to their homes had increased risks for neural tube defect-affected pregnancies [OR = 1.6 (95% CI = 1.1-2.5)] and limb anomalies [OR = 1.6 (95% CI = 1.0-2.7)]. Having a pet cat or dog and treating its fleas was not associated with increased anomaly risk. Women who reported living within 0.25 miles of an agricultural crop revealed increased risks for offspring with neural tube defects [OR = 1.5 (95%CI = 1.1-2.1)]. For many of the comparisons, data were sparse, resulting in imprecise effect estimation. Despite our investigating multiple sources of potential pesticide exposures, without more specific information on chemical and level of exposure, we could not adequately discriminate whether the observed effects are valid, whether biased exposure reporting contributed to the observed elevated risks, or whether nonspecific measurement of exposure was responsible for many of the observed estimated risks not being elevated.

Adult↗

PubMed1999

Maternal risk of breast cancer and birth characteristics of offspring by time since birth.

We examined the association between birth characteristics of offspring and the subsequent maternal risk of breast cancer in a population-based cohort of 998,499 women, 13 to 48 years of age at entry. There were 9,495 incident cases of breast cancer during 12.8 million person-years of follow-up among these women. Compared with mothers of singleton infants, mothers having a multiple birth had an increased risk of breast cancer in the first 5 years after a birth (relative risk (RR) = 1.8; 95% confidence interval (CI) = 1.1-2.8). The risk for mothers having a heavy-weighted child (>3.75 kg), as compared with a child of light weight (< or =3 kg), was also slightly increased (RR = 1.2; 95% CI = 0.9-1.5). This latter effect was primarily due to an increased incidence of tumors larger than 2 cm at diagnosis (RR = 1.4; 95% CI = 0.9-1.9). Our findings are compatible with the hypothesis that the hormonal level during pregnancy influences the risk of breast cancer in the early years after delivery.

Adolescent↗

PubMed1997

Impact of multiple antenatal doses of betamethasone on growth and development of mice offspring.

OBJECTIVE: Our purpose was to determine in a randomized, placebo-controlled manner whether multiple antenatal doses of betamethasone affect long-term growth and development of exposed mouse offspring. STUDY DESIGN: Sixty pregnant CD-1 mice received either two, four, or eight antepartum doses of 0.1 mg betamethasone or placebo. Perinatal outcomes, growth, and development of the offspring were compared in a blinded manner. Variables were compared by analysis of variance or chi 2 testing. RESULTS: Betamethasone-exposed subjects gained less weight during pregnancy and were delivered of fewer live pups, with fewer male survivors and lower birth weights. These trends were dose related. Growth measurements were similar after the neonatal period. No differences in functional development and physical maturation in the offspring were noted. The reproductive capability, perinatal outcomes, and growth and development of the second-generation offspring were unaffected by betamethasone exposure. CONCLUSION: Multiple antenatal dosings of betamethasone, reaching toxic levels, did not have an impact on the long-term growth and development of the surviving mouse offspring.

Animals↗

PubMed1978

The effects of chronic undernutrition over generations on rat development.

Experimental rats were fed 2/3 (10g/24 hours) of adlibitum diet throughout pregnancy and post-weaning, thus far for six generations; their brain and body development was compared with those of controls fed ad libitum (15.5 g/24 hours). As expected from previous reports, neonatal F1 offspring exhibited highly significant decreases in body weight, cerebral wet weight, cerebral DNA and cerebral protein. However, neonatal decreases were not greater in F2 through F6 than in F1 indicating that there was no cumulative effect of this undernutrition on offspring's parameters over generations. Maternal body weight at mating (90 days) and percentage of females that did not litter steadily decreased over generations. The observed high mortality in F1 through F6 and the resulting strong natural selection in favor of best mothers and weanlings could explain these findings. The phenomena contributing to high mortality are multiple and involve maternal factors during pregnancy and before weaning, as well as offspring factors.

Aging↗

PubMed2001

Prevalence, characteristics and diabetes risk associated with transient maternally acquired islet antibodies and persistent islet antibodies in offspring of parents with type 1 diabetes.

Accurate assessment of type 1 diabetes risk in young children requires discrimination between antibodies that are produced by the child and antibodies acquired through the placenta from an islet antibody-positive mother. We studied 682 offspring from mothers with type 1 diabetes and 329 offspring from fathers with type 1 diabetes and nondiabetic mothers for insulin (auto)antibodies, glutamic acid decarboxylase antibodies, and tyrosine phosphatase IA-2 antibodies before age 1 yr and again at age 2 yr to ascertain transience or persistence. Antibodies were detected at age 9 months in 5 (1.5%) offspring from fathers with type 1 diabetes; all were insulin (auto)antibodies only, all persisted and developed multiple antibodies, and 1 developed type 1 diabetes. In contrast, 31 (4.5%) offspring from mothers with type 1 diabetes had antibodies at 9 months; 12 (1.8%) persisted at age 2 yr, and 19 (2.8%) did not persist, suggestive of transient residual maternal antibodies. Multiple antibodies at 9 months were usually persistent (3 of 4 offspring), as were single insulin (auto)antibodies in offspring from mothers with type 1 diabetes (8 of 13 offspring), whereas persistent glutamic acid decarboxylase antibodies (1 of 12) and tyrosine phosphatase IA-2 antibodies (0 of 2) were rare. Offspring with persistent antibodies at age 9 months had a high type 1 diabetes risk (100% by age 5 yr for those with multiple antibodies and 27% for single antibodies at 9 months), whereas offspring with transient antibodies had 0% type 1 diabetes risk (P < 0.01). Transience was associated with very high antibody levels at birth. For insulin (auto)antibodies, the measurement of subclass was also informative. Residual maternal antibody was indicated by similar insulin (auto)antibodies subclasses at 9 months and at birth, whereas different subclasses were indicative of nonmaternal antibody. Moreover, the presence of IgG1-insulin (auto)antibodies was associated with antibody persistence and type 1 diabetes risk. These strategies are helpful in discriminating high and low risk antibodies before age 1 yr and should be important for prognosis and reducing unnecessary parent anxiety.

Autoantibodies↗

PubMed1992

A case-control study of paternal smoking and birth defects.

Although the influence of paternal smoking on birth defects is of great public interest, epidemiological evidence concerning this potential relationship is extremely limited. A stratified random sample of 29 hospitals in the Shanghai Municipality, China, was used to select 1012 birth defects cases and controls. Mothers of the cases and controls were interviewed in the hospitals from October 1986 to September 1987. A modest relationship between paternal smoking and overall birth defects in offspring was identified [odds ratio (OR) = 1.21, 95% confidence interval (CI): 1.01-1.45]. More markedly elevated risks were identified for anencephalus (OR = 2.1), spina bifida (OR = 1.9), pigmentary anomalies of the skin (OR = 3.3) and varus/valgus deformities of the feet (OR = 1.8). Our analysis also shows that paternal smoking is more likely to be associated with multiple rather than isolated malformations. A paternally-mediated effect of smoking on birth defects is suggested and further studies are encouraged.

Adult↗

PubMed2002

Congenital malformations in offspring of Vietnamese women in California, 1985-97.

BACKGROUND: Little is known about reproductive outcome risks for Vietnamese women delivering infants and fetuses in the U.S. METHODS: Using data from a large population-based registry, we explored risks of selected congenital malformation phenotypes in offspring of Vietnamese women in California. Data were derived from the California Birth Defects Monitoring Program, a population-based active surveillance system for collecting information on infants and fetuses with congenital malformations using multiple source ascertainment. Approximately 3.4 million births (liveborn and stillborn) occurred during the ascertainment period, 1985-97. Information on maternal race/ethnic background was obtained from California birth certificate and fetal death files. Vietnamese women delivered 45,453 births and 1,257,853 births were delivered to non-Hispanic white women. RESULTS: The overall prevalence of structural congenital malformations was 1.92 among Vietnamese and 2.63 among non-Hispanic whites per 100 births and fetal deaths. Grouping by 20 3-digit malformation codes of the International Classification of Diseases-Ninth Revision revealed relative risks of 0.8 or less for spina bifida, eye, upper alimentary, genital, urinary, musculoskeletal, "other" limb, and "other" musculoskeletal anomalies, and relative risks of 1.3 or more for anencephaly and chromosomal anomalies. Grouping by the more specific 4-digit malformation codes revealed 50, among 178, malformation groupings with associated relative risks of >or=1.3 or <or=0.8. Seventeen relative risk estimates suggested elevated risks for Vietnamese births, and 33 estimates suggested lowered risks for Vietnamese, relative to non-Hispanic white births. Simultaneous adjustment for maternal age, plurality, and child sex, did not substantially alter observed risks. CONCLUSIONS: These data contribute to a relatively sparse literature about an important subgroup of the U.S. population, but can not elucidate whether increased or decreased risks among Vietnamese are related to potential underlying genetic susceptibilities, to cultural, social, or political differences that could modify exposures, or to the many potential combinations between susceptibilities and exposures.

California↗

PubMed1995

Life-time exposure to dichlorvos affects behaviour of mature rats.

Wistar rats were exposed to dichlorvos [CAS number 62737]. Doses were 1/25; 1/50; and 1/100 LD50, that is 3.88; 1.94; 1.46; and 0.97 mg kg-1 DDVP, respectively, throughout gestation (GD1-birth) and during suckling via oral dosing to the dams, and then via the same doses by gavage for the rest of their lives. The offspring were tested in an open field (OF), a multiple T-maze, and in a 'novelty-induced-grooming' test to assess behavioural competence as adults. Dose-related increases in running time and incorrect choices in the maze were observed during the first 2 weeks of a 3-week study at 9-11 weeks of age. Horizontal activity was increased, vertical activity decreased, and defecation decreased in the OF at 9-12 weeks of age; these changes were again dose-related. Sleep was also affected at 12 weeks of age. AChE activity in the brain and in blood at sacrifice was roughly 40% to 65% of control, again reflecting the doses administered. The significantly changed behavioural profile of DDVP treated rats may serve as a useful biomarker to judge functional damage of CNS properties.

Acetylcholinesterase↗

PubMed1983

Gender after artificial induction of ovulation and artificial insemination.

Several studies on artificial insemination by donor (AID) semen have suggested that the gender of infants can be influenced by treatment of the women with clomiphene citrate (CC) and by the type of semen used (fresh versus cryopreserved). We conducted a 3-year prospective clinical trial to test these hypotheses. Two groups of pregnant women were evaluated. Group I (n = 130) comprised women whose ovulation was induced by CC; group II (n = 190) comprised those who conceived during spontaneous ovulatory cycles. In a total of 320 pregnancies, 55 spontaneous abortions occurred, 23.1% in group I and 13.2% in group II (P less than or equal to 0.05). Two tubal ectopic pregnancies occurred in group I. Of the 100 and 165 pregnancies carried to term in the treated and control groups, respectively, 11% and 1.8% involved twins (P less than or equal to 0.005). When only single births were considered, group I had 46.1% males in 89 term pregnancies, and group II had 60.5% males in 162 term pregnancies. Significantly more female offspring occurred in the group treated with CC (P less than or equal to 0.05). Because it is possible that a portion of the effects observed in this study were a function of cryopreservation of the AID semen, we compared data on frozen sperm with data on fresh sperm in terms of abortion, gender, and incidence of multiple births; there were no significant differences. Fertil Steril 40:481, 1983.

Clomiphene↗

PubMed1980

Multiple sclerosis in a migrant population: 2. Half-orientals immigrating in childhood.

We studied offspring of Vietnamese mothers and French fathers who had been born in Vietnam and brought to France to be raised. All but 72 of 3,451 such individuals completed background and neurological questionnaires. Those with positive answers on the latter were examined neurologically. The median year of birth for the 3,379 respondents was 1948, the median year of arrival in France was 1957, and they had resided in France a median of 18 years before interview in 1975. Twenty-five persons had neurological symptoms, and 6 others reported a history of seizures alone. A total of 16 reported seizures: 7 with infantile febrile fits and 9 with afebrile seizure disorders. Three cases of exacerbating-remitting multiple sclerosis (MS) were discovered as well as 3 persons in whom MS was suspected: 1 with cervical myelopathy, 1 with progressive paraparesis, and 1 with bilateral optic neuropathy. The 3 MS cases provided a crude prevalence rate (or 18-year cumulative risk) of 89 per 100,000. Their age-specific prevalence rate was 169 per 100,000 population aged 20 through 29 years. Each measure was similar to such rates for Denmark and had lower 95% confidence limits that clearly exceeded expectations for Vietnam. The results provide further evidence that the risk of MS can be increased by migration in childhood from low- to high-risk regions.

Adolescent↗

PubMed2001

Birth of MHC-defined rhesus monkeys produced by assisted reproductive technology.

One of the best animal approaches for testing HIV vaccines is the challenge of vaccinated rhesus macaques with SHIV or SIV. Production of rhesus macaques in which all of the MHC class I and II alleles are known represents an opportunity to characterize the entire immune response to SIV and should be an invaluable resource for understanding pathogenesis and vaccine-induced immune responses. Unfortunately, there are few MHC-defined rhesus macaques available for vaccine research. Selective breeding supports the production of limited numbers of macaques that express particular MHC class I alleles. If both parents express the allele of interest, only three quarters of the offspring will express the same allele. However, assisted reproductive technologies, such as in vitro fertilization (IVF) and embryo transfer, can be used for production of MHC-defined macaques, expressing multiple MHC class I and II molecules for which SIV peptides, tetramers and ELISPOT assays exist. Here, we report the birth of MHC-defined rhesus monkeys produced by assisted reproductive technology. Continued improvements in assisted reproductive technologies in rhesus monkeys will enable us to develop a unique prototypic animal production program for the creation of MHC-defined and genetically-identical monkeys for vaccine research.

Animals↗

PubMed1991

Do male patients with multiple sclerosis have an excess of female offspring?

In a nationwide epidemiological study, 2,506 men and 5,296 women with multiple sclerosis (MS) completed a questionnaire concerning disease course and reproductive history. The mean number of children was the same for both men and women (1.7). The sex ratio for offspring of male probands was 0.99; it was significantly lower than that of offspring of female probands (1.07). As the sex ratio of French births is 1.05, the observed difference seemed due to an altered sex ratio in fathers with MS. This atypical sex ratio of births for male patients was examined in relation to MS course. We found that it was mainly due to an excess of female births after the onset of the disease. Altered sex ratio and MS might have some risk factors in common.

Adult↗

PubMed2024

Prenatal cannabis exposure is associated with alterations in offspring DNA methylation at genes involved in neurodevelopment, across the life course.

Prenatal cannabis exposure (PCE) is of increasing concern globally, due to the potential impact on offspring neurodevelopment, and its association with childhood and adolescent brain development and cognitive function. However, there is currently a lack of research addressing the molecular impact of PCE, that may help to clarify the association between PCE and neurodevelopment. To address this knowledge gap, here we present epigenome-wide association study data across multiple time points, examining the effect of PCE and co-exposure with tobacco using two longitudinal studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Christchurch Health and Development Study (CHDS) at birth (0 y), 7 y and 15-17 y (ALSPAC), and ~27 y (CHDS). Our findings reveal genome-wide significant DNA methylation differences in offspring at 0 y, 7 y, 15-17 y, and 27 y associated with PCE alone, and co-exposure with tobacco. Importantly, we identified significantly differentially methylated CpG sites within the genes LZTS2, NPSR1, NT5E, CRIP2, DOCK8, COQ5, and LRP5 that are shared between different time points throughout development in offspring. Notably, functional pathway analysis showed enrichment for differential DNA methylation in neurodevelopment, neurotransmission, and neuronal structure pathways, and this was consistent across all timepoints in both cohorts. Given the increasing volume of epidemiological evidence that suggests a link between PCE and adverse neurodevelopmental outcomes in exposed offspring, this work highlights the need for further investigation into PCE, particularly in larger cohorts.

DNA Methylation↗

PubMed1988

Steroid contraceptive use and pregnancy outcome.

Contraceptive use in relation to pregnancy outcome was studied in 8,816 births in Chiang Mai, northern Thailand, by examination of newborn infants and interviews with their mothers. Four thousand twenty-three women used no contraception before the index pregnancy, 1,229 used the injectable contraceptive Depo Provera (DMPA), and 3,038 used oral contraceptives prior to or during pregnancy. No differences were observed between these groups with respect to still births, multiple pregnancies, and birthweight. Women who used oral contraceptives had unexpectedly low rates of major defects and may have been affected by self-selection bias, whereas the noncontraceptors had rates similar to other populations. There was a significantly increased association of polysyndactyly among infants of DMPA users relative to the other groups, which was most pronounced in offspring of women under age 30 years, and persisted after exclusion of subjects with a family history or infants with multiple abnormalities. However, in five out of the ten polysyndactyly cases, the last injection of DMPA occurred more than 9 months before conception, and only three cases had definite gestational exposure. The association of chromosomal anomalies was also significantly increased in infants of mothers who used DMPA. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptional exposure to DMPA in many cases, and chance effects due to multiple statistical comparisons make a causal association unlikely. Other birth defects that had been previously reported in some publications to be associated with progestational steroid exposure, such as neural tube defects, heart malformations, and limb reduction defects, were not found in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗