William S. Bradshaw

Developmental toxicity of nine selected compounds following prenatal exposure in the mouse: naphthalene-, p-nitrophenol, sodium selenite, dimethyl phthalate, ethylenethiourea, and four glycol ether derivatives

Ethylene glycol dimethyl ether (EGdiME), diethylene glycol dimethyl ether (diEGdiME), triethylene glycol dimethyl ether (triEGdiME), diethylene glycol diethyl ether (diEGdiEE), ethylenethiourea (ETU), sodium selenite (SS), dimethyl phthalate (DMP), naphthalene (NAP), or p-nitrophenol (PNP) were administered by gavage for eight consecutive days to female CD-1 mice. Weight loss was insensitive as an index of sublethal adult toxicity and was inadequate for determining a maximum tolerated dose. LD50 values indicate that SS, NAP, and PNP were more toxic (8.4, 353.6, and 625.7 mg/kg, respectively) than the polyglycol ethers, ETU, and DMP (LD50 values ranged from 2525.8 to 6281.9 mg/kg). Each of the compounds was administered on d 7 through 14 to pregnant animals at a single dose estimated to be at or just below the threshold of adult lethality. In such a reproductive study, each of the compounds could be categorized on the basis of the pattern of maternal lethality and fetotoxicity which it produced. The number of dams with complete resorptions was significantly increased after administration of ETU, and no mice in the EGdiME-, diEGdiME-, or triEGdiME-treated groups delivered any viable offspring. Maternal lethality was significant in the EGdiME, triEGdiME, PNP, and NAP groups. There was a slight reduction in the average number of live pups per litter in the diEGdiEE- and PNP-treated groups and a significant reduction in the NAP group. The number dead per litter was increased with diEGdiEE. SS and DMP had no effect on maternal or fetal survival at the doses administered. Individual pup weight at d 1 postpartum was only significantly reduced by diEGdiEE, and no gross congenital abnormalities were detected in neonates from any treatment group. These results provide guidelines for the subsequent toxicity testing of these chemicals.

Sexual orientation change efforts among current or former LDS church members

This study examined sexual orientation change efforts (SOCE) by 1,612 individuals who are current or former members of the Church of Jesus Christ of Latter-day Saints (LDS). Data were obtained through a comprehensive online survey from both quantitative items and open-ended written responses. A minimum of 73% of men and 43% of women in this sample attempted sexual orientation change, usually through multiple methods and across many years (on average). Developmental factors associated with attempts at sexual orientation change included higher levels of early religious orthodoxy (for all) and less supportive families and communities (for men only). Among women, those who identified as lesbian and who reported higher Kinsey attraction scores were more likely to have sought change. Of the 9 different methods surveyed, private and religious change methods (compared with therapist-led or group-based efforts) were the most common, started earlier, exercised for longer periods, and reported to be the most damaging and least effective. When sexual orientation change was identified as a goal, reported effectiveness was lower for almost all of the methods. While some beneficial SOCE outcomes (such as acceptance of same-sex attractions and reduction in depression and anxiety) were reported, the overall results support the conclusion that sexual orientation is highly resistant to explicit attempts at change and that SOCE are overwhelmingly reported to be either ineffective or damaging by participants.

Navigating Sexual and Religious Identity Conflict: A Mormon Perspective

This study examined navigation of sexual and religious identity conflict among 1,493 same-sex attracted current or former members of the Church of Jesus Christ of Latter-day Saints. Participants were classified into four groups: (a) rejected a lesbian, gay, or bisexual identity (5.5%); (b) compartmentalized sexual and religious identities (37.2%); (c) rejected religious identity (53%); and (d) integrated religious and sexual identities (4.4%). Systematic differences emerged among the groups in sexual identity development histories, developmental milestones, relationship experiences, religious engagement, and psychosocial health. The findings suggest that rejection or compartmentalization of sexual identity may be difficult to sustain over time and likely comes at a significant psychosocial cost. Integration of identities may be equally difficult to achieve, and appears to be associated with optimal outcomes.

NSAID-Induced Apoptosis in Rous Sarcoma Virus-Transformed Chicken Embryo Fibroblasts is Dependent on v-src and c-myc and is Inhibited by bcl-2

Mounting epidemiological and experimental evidence implicates non-steroidal antiinflammatory drugs as anti-tumorigenic agents. Our previous work showed that nonsteroidal antiinflammatory drug treatment of src-transformed chicken embryo fibroblasts caused apoptosis--a mechanism by which these drugs might exert their anti-tumorigenic effect. The present studies employ a sensitive technique for detecting single- and double-stranded DNA cleavage (the comet assay) to quantitate apoptosis. By this method pp60v-src, which antagonizes apoptosis in many cell systems, was found to induce apoptosis in 11-23% of serum-starved fibroblasts. However, treatment with diclofenac following pp60v-src activation produced a much stronger response beginning within 6 hours of treatment that resulted in 100% lethality. During cell death, cyclooxygenase-2 but not cyclooxygenase-1 mRNA was found to be uniformly increased by all apoptotic drugs tested. Examination of the expression of apoptosis-associated genes showed that c-rel and p53 (found in normal or v-src-transformed chicken embryo fibroblasts at moderate levels), and bcl-2 (present at an extremely low level) were largely unchanged by treatment with eight different nonsteroidal antiinflammatory drugs. However, overexpression of human bcl-2 inhibited diclofenac-mediated apoptosis by 90%, demonstrating directly that bcl-2 expression can regulate nonsteroidal antiinflammatory drug induction of cell death. The proto-oncogene c-myc is known to cause apoptosis in chicken embryo fibroblasts when artificially overexpressed in cells deprived of trophic factors. We found that nonsteroidal antiinflammatory drug treatment following pp60v-src activation persistently induced myc protein and mRNA by more than 20-fold above that evoked by pp60v-src activation alone. Moreover, transfection of antisense c-myc oligonucleotides reduced drug-induced myc expression by 80% and caused a concomitant 50% reduction in cell death. These findings suggest that nonsteroidal antiinflammatory drug-induced apoptosis proceeds through a src/myc dependent pathway which is negatively regulated by bcl-2.

IN VIVO AND IN VITRO EXPRESSION OF A NON-MAMMALIAN CYCLOOXYGENASE-1

Unlike cyclooxygenase 2 (COX-2), COX-1 has never been identified, purified or cloned in a non-mammalian species. Here we report the RT-PCR cloning of a chicken cDNA that encodes the amphipathic membrane binding region and parts of the dimerization and catalytic domains of COX-1-like enzyme. Sequence comparison showed this putative COX-1 to be evolutionarily less conserved than COX-2. Furthermore, whereas COX-1 in mammals is broadly expressed in tissues as a constitutive enzyme, the mRNA detected by our clone in chicken was almost absent in tissues and embryo fibroblasts (CEF). Highest expression was in brain and seminal vesicle. This transcript was not detectable during chick embryogenesis and, as is the case for mammalian COX-1, was not induced above background by mitogen stimulation. The identification of an avian COX-1 shows that COX-1 and COX-2 existed as separate catalysts for prostaglandin synthesis before the divergence of birds and mammals.

Alterations in liver ultrastructure and induction of UDP-glucuronyltransferase in the rat following prenatal exposure to 3,4,3′,4′-tetrachlorobiphenyl

Prenatal exposure of rats to 3,4,3′,4′-tetrachlorobiphenyl (4CB) at 3 mg/kg/day from day 6 through day 18 of gestation produced a high incidence of perinatal mortality. Although the fine structure of fetal liver at day 19 appeared normal, significant changes were manifest in newborn pups. These alterations included a distention of cisternae of the rough endoplasmic reticulum and conspicuous proliferation of smooth membrane elements, which persisted in survivors for several weeks. In addition, mitochondria often appeared condensed with an atypical distribution of cristae. These changes were accompanied by a postnatal induction in the activity of liver UDP-glucuronyltransferase. In treated litters, 3-week-old pups had activity levels of the enzyme three times that of the controls.

An evaluation of various treatments to increase sperm penetration capacity for potential use in an in vitro fertilization program

OBJECTIVE To select in vitro fertilization (IVF) patients with a low sperm penetration assay (SPA) value and to determine if the penetration rate, fertilization rate, and the pregnancy rate (PR) can be improved in these patients by treating sperm with refrigeration, calcium ionophore A23187, prostaglandin E1, prostaglandin E2, or heparin. DESIGN The study consists of three parts: identification of patients with poor SPA values, analysis of treatments to improve the SPA value, and evaluation of the treatments to improve fertilization and PRs. RESULTS The data indicate that treatment of sperm with refrigeration can improve fertilization and PRs during IVF in selected patients previously shown to have an improved SPA value with the treatment. CONCLUSIONS Three points are emphasized: (1) the treatments analyzed in this study can improve SPA values in some of the patients with low sperm penetration capacity; (2) of the treatments studied, sperm refrigeration resulted in the largest improvement in sperm penetration capacity; and (3) sperm refrigeration can increase fertilization and PRs during IVF in this select group of patients.

Perinatal toxicity of ethylene glycol dimethyl ether in the rat

Ethylene glycol dimethyl ether (EGdiME) was administered by gavage to pregnant Sprague-Dawley rats in doses of 30, 60, 120, 250, 500, and 1000 mg/kg/day from day 8 through day 18 of gestation. The effects of the compound on maternal weight gain, length of gestation, perinatal mortality, teratogenicity, average fetal weight on day 19, and average pup weight one day after birth were assessed. A clear pattern of dose-dependent maternal and fetal toxicity was observed. EGdiME caused maternal deaths at 1000 mg/kg/day and was fetolethal at doses ranging from 120 to 1000 mg/kg/day. A dose of 60 mg/kg/day resulted in a 7% weight decrease and severe edema in pups surviving to birth. Skeletal examinations in this group revealed fetotoxicity as evidenced by the lack of ossified bone, but there was no indication of anomalies in soft tissues. The same concentration in dams allowed to go to term resulted in a delay in the onset of parturition and produced litters with only one-third the number of live pups as controls. Of these, an average of less than 1 per litter survived to day 1 postpartum. The compound was not fetolethal on day 19 at a dose level of 30 mg/kg/day. Perinatal mortality in the interval between day 19 of gestation and birth was manifested, however, by an average reduction of 2 live pups per litter at birth. There was a close correlation between the fetotoxic effects of the various concentrations and the degree to which the maternal weight gain pattern of each departed from the control profile.

Psychosocial Correlates of Religious Approaches to Same-Sex Attraction: A Mormon Perspective

This study examined the psychosocial correlates of following various church-based approaches for dealing with same-sex attraction, based on a large sample (1,612) of same-sex attracted current and former members of the Church of Jesus Christ of Latter-day Saints (LDS, or Mormon). Overall, this study found that biologically based views about the etiology of same-sex attraction (vs. psychosocial views), LDS church disaffiliation (vs. activity), sexual activity (vs. celibacy), and legal same-sex marriage (vs. remaining single or mixed-orientation marriage) were all associated with significantly higher levels of self-esteem and quality of life, and lower levels of internalized homophobia, sexual identity distress, and depression. The divorce rate for mixed-orientation marriages was 51% at the time of survey completion, with projections suggesting an eventual divorce rate of 69%.

Sexual Orientation Change Efforts Through Psychotherapy for LGBQ Individuals Affiliated With the Church of Jesus Christ of Latter-day Saints

This study reports the results of a comprehensive online survey of 1,612 current or former members of the Church of Jesus Christ of Latter-day Saints, many of whom engaged in psychotherapy to cope with (i.e., understand, accept, or change) their same-sex attractions. Data obtained from written and quantitative responses showed that therapy was initiated over a very wide age range and continued for many years. However, counseling was largely ineffective; less than 4% reported any modification of core same-sex erotic attraction. Moreover, 42% reported that their change-oriented therapy was not at all effective, and 37% found it to be moderately to severely harmful. In contrast, affirming psychotherapeutic strategies were often found to be beneficial in reducing depression, increasing self-esteem, and improving family and other relationships. Results suggest that the very low likelihood of a modification of sexual orientation and the ambiguous nature of any such change should be important considerations for highly religious sexual minority individuals considering reorientation therapy.