Biomedical subjects
D R Mattison
Publications and source records attributed to D R Mattison.
The effect of benzo(a)pyrene on murine ovarian and corpora lutea volumes.
OBJECTIVE: Women who smoke have impaired fertility and experience menopause at an earlier age. This experiment determined the effect of benzo(a)pyrene, a polycyclic aromatic hydrocarbon contained in cigarette smoke, on murine ovarian volume, total corpora lutea volume, individual corpora lutea volumes, and corpora lutea numbers. STUDY DESIGN: C57BL/6N mice were treated with intraperitoneal injections of 0 to 500 mg/kg benzo(a)pyrene in corn oil. The 20 mice at each dose were divided into four groups of five each and were killed at 1, 2, 3, or 4 weeks after treatment. Ovaries were serially sectioned and analyzed morphometrically. RESULTS: Benzo(a)pyrene produced a dose- and time-dependent decrease in ovarian volume, total corpora lutea volume, and number of corpora lutea per ovary. This effect was transitory at low doses with complete recovery of corpora lutea by 4 weeks. Compensatory hypertrophy of the individual corpora lutea occurred during the recovery phase. Ovarian function did not return in animals treated with the two highest doses. CONCLUSION: Benzo(a)pyrene is a murine ovarian toxicant that inhibits corpus luteum formation in a dose- and time-dependent fashion.
Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 1. Effects on ovarian structure and function.
The antineoplastic alkylating agent, cyclophosphamide (CPA) is known to impair normal female reproductive function. We have examined the time- and dose-dependent effects of CPA on the ovary, specifically, its impact on follicle numbers, ovarian morphometrics, and estradiol (E2) production. Female C57BL/6N mice were treated ip with CPA in normal saline at doses of 0, 75, 200, or 500 mg/kg. Ovaries were removed 1 to 14 days following treatment and serial sections were prepared. Differential follicle counts revealed that primordial follicles were most sensitive to CPA (ED50 = 122 mg/kg), followed by antral and growing follicles. Primordial follicles were affected by all doses of CPA and were completely destroyed by 3 days in the 500 mg/kg dose group. The greatest reduction in antral follicles was to 49% and 7% of controls by CPA doses of 200 and 500 mg/kg, respectively. Plasma E2 concentrations correlated best with antral follicle numbers (r2 = 0.94) and antral follicle volume (r2 = 0.88). Growing follicles were least sensitive to CPA and only decreased at 7 and 14 days. Although atretic changes were observed in growing follicles after treatment with CPA, these follicles recovered and progressed into apparently functional antral follicles (that is, they produced E2). Total ovarian volume was significantly reduced (30 to 40%) in the high-dose group on day 1, and remained depressed throughout the experiment. Examination of ovarian morphometrics indicated that this volume loss represented specific temporal changes in corpora lutea (CL), interstitial tissue, growing follicles, and antral follicles. At 1 and 3 days after treatment, the major loss in ovarian volume was due to a reduction in antral follicle and interstitial tissue volumes, while at 7 days the majority of volume loss was accounted for by the absence of CL. It is not known if CL are directly affected by CPA at the early time points, but their absence at 7 and 14 days is probably due to earlier destruction of antral follicles. These results demonstrate that CPA-induced ovarian toxicity is exhibited as temporal changes in both structural and functional features of the ovary, particularly in destruction of primordial and antral follicles and depressed E2 production. Information of this type also gives insight into ovarian response to chemical disruption of folliculogenesis and its recovery process.
Reproductive toxicity of cyclophosphamide in the C57BL/6N mouse: 2. Effects on uterine structure and function.
Cyclophosphamide-induced uterine weight loss was evaluated to determine whether it was a function of primary toxicity to the uterus or a secondary response to ovarian toxicity, that is, antral follicle destruction. C57BL/6N mice treated with cyclophosphamide exhibited a reduction in uterine weight concurrent with a decrease in plasma estradiol (E2) concentrations, thereby indicating toxicity to the ovary. However, when E2 concentrations recovered, uterine weight still remained depressed, suggesting that cyclophosphamide also impaired uterine function. Further investigation revealed that cyclophosphamide altered the normal uterotropic response to E2, significantly diminishing the uterine weight gain associated with E2 treatment. We conclude that effects of cyclophosphamide on the uterus involve two components: 1) decreased uterine weight in response to decreased plasma E2 resulting from ovarian toxicity, and 2) an altered response to E2 due to direct uterine toxicity.
Protecting reproductive and developmental health under Proposition 65--public health approaches to knowledge, imperfect knowledge, and the absence of knowledge.
Explore the source record for details and available documents.
Morphometric assessment of the murine ovarian toxicity of 7,12-dimethylbenz(a)anthracene.
7,12-Dimethylbenz(a)anthracene (DMBA) is a polycyclic aromatic hydrocarbon and a component of cigarette smoke that has been identified as a murine reproductive toxicant. The morphometric parameters of total ovarian volume, individual corpus luteum volumes, and total corpora lutea volume were measured in C57BL/6N mice treated with DMBA. Each group received single intraperitoneal injections of 0, 0.1, 1.0, or 10 mg/kg and were sacrificed at 1, 2, 3, or 4 weeks after treatment. DMBA produced a dose-dependent decrease in ovarian volume and number of corpora lutea in each ovary. The observed reduction in total corpora lutea volume did not fully account for the loss in total ovarian volume. This is consistent with previous descriptions of a toxic effect on all ovarian components including growing and resting follicles. Growing follicles that escaped the toxic effects of DMBA and achieved ovulation resulted in a corpus luteum that appeared histologically normal. Morphometric analysis of this animal model further defines the dynamic changes in the mouse ovary in response to DMBA.
MR imaging in high-risk obstetric patients: a valuable complement to US.
The accuracy of prenatal diagnosis has become increasingly critical in the field of high-risk obstetrics. Although ultrasound (US) provides adequate information in most cases and continues to be the initial prenatal examination of choice, there are instances in which the results of the US study may be equivocal. The role of magnetic resonance (MR) imaging was explored in 27 selected patients with various indications to determine its effectiveness as a complement to US. MR imaging was most helpful in the diagnosis of extrauterine gestation, evaluation of placental position, determination of extent or nature of masses associated with pregnancy, and differentiation between diaphragmatic hernia and a thoracic mass. Although MR imaging did not add information that affected the accuracy of the diagnosis of oligohydramnios, in all other cases it provided an extra dimension in diagnosis by showing clearer anatomic relationships in the pelvis. It has proved to be a valuable complement to an equivocal US study.
Pesticide concentrations in Arkansas breast milk.
During an episode of pesticide dairy product contamination in Arkansas in 1986, breast milk samples from 942 women were analyzed for concentrations of chlorinated pesticides. The pesticides found most frequently in quantifiable concentrations were p,p'-DDE (100%), oxychlordane (84%), trans-nonachlor (77%), heptachlor epoxide (74%) and beta-HCH, an isomer of lindane (27%). The pesticides present in highest mean concentrations of all samples analyzed (reported as ppm in milk fat) were p,p'-DDE (0.952 ppm), trans-nonachlor (0.062 ppm), oxychlordane (0.051 ppm), heptachlor epoxide (0.045 ppm), p,p'-DDT (0.039 ppm), and beta-HCH (0.032 ppm). These concentrations are lower than previous reports from similar regions of the US. However, continued persistence in human breast milk is of concern due to potential adverse health effects from these chemicals.
Phosphoramide mustard is responsible for the ovarian toxicity of cyclophosphamide.
Although cyclophosphamide (CPA) is an ovarian toxicant, the responsible metabolite(s) have not been identified. The purpose of these experiments was to determine if phosphoramide mustard or acrolein were the proximate toxicants produced by metabolic activation of CPA. To do this analogs of CPA known to generate either phosphoramide mustard or acrolein in vivo were assessed for their ability to produce ovarian toxicity as measured by differential follicle destruction, ovarian volume loss, and uterine weight loss and compared to the effects produced by CPA. Phosphoramide mustard cyclohexylamine salt (PMC) and trans-4-phenylcyclophosphamide (T4P), both of which generate phosphoramide mustard, and didechlorocyclophosphamide (DCPA) and allyl alcohol (AA) which generate acrolein were administered ip to female C57BL/6N mice, 10-12 weeks old, at doses equimolar to 0, 25, 75, 200, or 500 mg/kg of CPA. Three days later the animals were killed, their uterine weights measured and their ovaries removed, fixed, and serially sectioned. Only PMC and T4P produced ovarian toxicity. On an equimolar basis these compounds were over twice as potent as CPA. Both caused a significant reduction in uterine weight (to 50% of controls) at doses of 200 (PMC) and 150 mg/kg (T4P). PMC and T4P also caused a 50% reduction in ovarian volume at doses above 75 mg/kg. Primordial follicles were most sensitive; ED50s were 76.9, 25.3, and 19.3 mg/kg (0.276, 0.091, and 0.069 mmol/kg) for CPA, PMC, and T4P, respectively. Growing follicle numbers were also reduced by T4P and PMC, an effect not seen with CPA treatment. Finally, antral follicles were significantly reduced by all doses of PMC, and with T4P at doses greater than 75 mg/kg. The highest doses of PMC, T4P, and CPA all caused a reduction in antral follicle numbers to less than one percent of controls. Didechlorocyclophosphamide (DCPA) and allyl alcohol (AA), compounds that generate acrolein but not phosphoramide mustard in vivo, had no effect on any of the parameters measured even when injected directly into the ovary. This suggests that phosphoramide mustard is responsible for CPA ovarian toxicity. The greater potency of PMC and T4P compared to CPA is likely the result of these compounds bypassing important detoxification steps, therefore, more of the parent compound reaches the ovary as the toxic metabolite.
Hepatic bioactivation of 4-vinylcyclohexene to ovotoxic epoxides.
Explore the source record for details and available documents.
Physiological alterations during pregnancy: impact on toxicokinetics.
The physiological changes that occur in the alimentary, cardiovascular, pulmonary, and renal organ systems during pregnancy are designed to increase availability of nutrients to and remove wastes from the fetus. Although this is a general requirement, not all animals use the same strategies to meet these goals. These physiological adaptations will impact on toxicokinetics and may alter toxicodynamics. Absorption, distribution, metabolism, transfer between maternal and fetal compartments, and elimination will change for many xenobiotics during pregnancy. The changes in body weight, total body water, plasma proteins, body fat, and cardiac output will alter the distribution of many xenobiotics (Hytten and Leitch, 1971; Hytten and Chamberlain, 1980; Mattison, 1986). As the toxicokinetic parameters change across species, it is important to understand their impact on chemicals associated with maternal, placental, and fetal toxicity for appropriate cross-species extrapolation.
Comparison of random and serial sections in assessment of ovarian toxicity.
Assessment of ovarian toxicity by follicle quantitation and morphometric analysis of serial sections is time consuming and expensive. This report compares the estimation of follicle number obtained from counting oocytes in serial sections or 5 random sections of mouse ovaries. Ovaries were obtained from C57BL/6N and B6C3F1 mice treated with ovarian toxicants. C57BL/6N mice were treated with cyclophosphamide (0, 75, 200, and 500 mg/kg, ip) and killed at 24, 72, and 168 h. B6C3F1 mice were treated daily, ip, with 4-vinylcyclohexene (0, 100, 400, and 800 mg/kg/day for 30 days), vinylcyclohexene diepoxide (0, 10, 40, and 80 mg/kg/day for 30 days), or benzo(a)pyrene (100 mg/kg, single dose) and killed on day 31. Ovarian serial sections were prepared and oocytes counted in every tenth section. When serial sections were evaluated, 30 to 60 sections were counted. Random section counting involved randomly selecting 5 sections from the 30 to 60 sections previously counted by the serial method. Chemically-induced follicle loss was evident by the reduction in follicle counts relative to control animals when estimating follicle number using serial or random section counting. Furthermore, a linear regression analysis of follicle counts over all treatment groups showed that the highest correlation between random and serial section counting and was for primordial follicles. Correlation coefficients (R2) for each follicle type were: primordial--C57BL/6N 0.82, B6C3F1 0.86; growing--C57BL/6N 0.16, B6C3F1 0.46; antral--C57BL/6N 0.07, B6C3F1 0.11. Although other screens may need to be developed for growing and antral follicles, primordial follicle toxicity is adequately defined by counting 5 random sections.
Oxytocin pharmacodynamics: effect of long infusions on uterine activity.
Despite common use in obstetrics for almost 50 years, there is still disagreement concerning optimal clinical protocols for the use of oxytocin. This disagreement arises in part from inadequate data on oxytocin pharmacokinetics and pharmacodynamics. This report evaluates the uterine response to fixed doses of oxytocin (1-3 mIU/min) over long infusion times (up to 120 min) in 10 patients with secondary arrest of dilatation. The uterine activity increased from 132 +/- 61 Alexandria units during the control period to 199 +/- 64 Alexandria units at an infusion rate of 1 mIU/min. Increasing the infusion rate to 2 mIU/min increased the uterine activity to 240 +/- 64 Alexandria units. The uterine activity increased until a steady state was achieved between 40 and 70 min after the initiation of infusion. Continuing the infusion at a fixed rate for more than 90 min appears to result in a decreasing uterine activity. Patients requiring oxytocin for augmentation of labor developed adequate uterine activity with dose rates of 1-3 mIU/min. Clinical protocols for oxytocin augmentation with an interval of 40-60 min between increases in the dosing seem reasonable based on these pharmacodynamic data.
An overview on biological markers in reproductive and developmental toxicology: concepts, definitions and use in risk assessment.
Reproduction and development are complex couple-dependent processes. Risk assessment for these health outcomes requires the use of biomarkers to link exposures to disease. Biological markers of susceptibility, external dose, internal dose, biologically effective dose, early or late biological responses, altered reproductive or developmental function, and reproductive or developmental disease are introduced. Using these biomarkers it is possible to define a biologically based risk assessment methodology for reproductive and developmental toxicity. Risk assessment for reproductive toxicity requires definition of male and female fecundity, couple-specific factors, spontaneous abortion rate, and other factors. Using using sperm count as a biomarker for male fecundity, an example of a reproductive risk assessment using biomarkers is performed.
The role of epoxidation in 4-vinylcyclohexene-induced ovarian toxicity.
4-Vinylcyclohexene (VCH) is present in gases discharged during synthetic rubber production. Chronic treatment of B6C3F1 mice and F-344 rats with VCH by gavage has been shown to induce ovarian tumors in mice but not in rats. Our objective was to understand the mechanism of the species difference in VCH-induced ovarian tumors. Since a critical step in the induction of ovarian tumors is destruction of the small oocyte, small oocyte counts obtained from serially sectioned ovaries were used as an index of toxicity. VCH or its epoxide metabolites [VCH-diepoxide, VCH-1,2-epoxide, and VCH-7,8-epoxide (in mice only)] were given to 28-day-old female mice and rats in corn oil, ip, at doses ranging from 0.07 to 7.4 mmol/kg body wt/day for 30 days. The dose which reduced the small oocyte count to 50% that of control was defined as the ED50. In mice, the ED50 for the reduction in small oocytes by VCH was 2.7 mmol/kg, whereas, no detectable oocyte loss occurred in rats at the highest dose of VCH (7.4 mmol/kg). The potency of the epoxides of VCH was greater than that of VCH in both species. The ED50 for oocyte loss by VCH-1,2-epoxide in mice and rats was 0.5 and 1.4 mmol/kg, respectively. In mice, VCH-7,8-epoxide had comparable potency to VCH-1,2-epoxide (ED50 = 0.7). VCH diepoxide was even more potent with ED50 values of 0.2 and 0.4 mmol/kg, in mice and rats, respectively. The dose response of the blood concentration of VCH-1,2-epoxide in mice after VCH showed that doses of VCH which caused minimal toxicity had the lowest blood level of this ovotoxic epoxide. Pretreatment of mice with the cytochrome P450 inhibitor chloramphenicol (200 mg/kg, ip) inhibited VCH epoxidation in vivo and in vitro and partially protected mice from VCH toxicity. Thus it appears that metabolism of VCH to epoxides and their subsequent destruction of oocytes are critical steps in VCH-induced ovarian tumors. Rats may be resistant to ovarian tumor induction by VCH because the amount of VCH converted to epoxides is insufficient to produce oocyte destruction.
Eliciting principles of hazard identification from experts.
National experts in the field of developmental toxicology were interviewed in order to elicit the principles, or rules-of-thumb, they use in determining if a compound or agent is likely to be a developmental hazard during pregnancy. Several levels of individual and cumulative consensus activity were carried out that resulted in consensus in 71 rules and partial consensus in an additional 24 rules of 145 rules initially elicited. Rules could be divided generically into those affecting the expert's confidence in a piece of scientific evidence and those determining the weight of importance of that evidence in deciding about hazard identification. Topically, the rules also divided into those about the general nature or characteristics of a compound, animal studies testing for an effect of the compound, and human reports about the presence of absence of developmental effects associated with the compound. Several conclusions about the methodology include the following: 1) expert systems must be based on the knowledge of more than one expert; 2) considerable human effort is expended in evaluating the certainty of scientific evidence before combining the evidence for problem solving; 3) how experts use evidence of different degrees of uncertainty in their decisions is a major area that is yet to be determined and that may greatly affect subsequent efforts in artificial intelligence; and 4) knowledge elicitation by interview has limitations but is a workable methodology for medical decision making.
Criteria for identifying and listing substances known to cause reproductive toxicity under California's Proposition 65.
Explore the source record for details and available documents.
Reproductive toxicity: male and female reproductive systems as targets for chemical injury.
On the basis of current knowledge of reproductive biology and toxicology, it is apparent that chemicals affecting reproduction may elicit their effects at a number of sites in both the male and the female reproductive system. This multiplicity of targets is attributable to the dynamic nature of the reproductive system, in which the hypothalamic-pituitary-gonadal axis is controlled by precise positive and negative feedback mechanisms among its components. Interference by a xenobiotic at any level in either the male or the female reproductive system may ultimately impair hypothalamic or pituitary function. Normal gonadal processes such as spermatogenesis or oogenesis, ejaculation or ovulation, hormone production by Leydig or granulosa cells, and the structure or function of the accessory reproductive structures (e.g., epididymis, fallopian tube) also appear vulnerable to xenobiotics. The reproductive system is a complex one that requires local and circulating hormones for control. This brief review illustrates a system for characterizing the mechanism of action of reproductive toxicants, as well as for defining the sites available for disruption of reproduction. Unfortunately, at present, data addressing the actual vulnerability of reproduction are sorely lacking. However, when experiments have been conducted and combined with epidemiologic data or clinical observation, it has been possible to demonstrate impairment of reproductive processes by xenobiotics. The role of environmental exposure to xenobiotics in the increase in infertility that has been observed remains to be defined.