Jerrold Heindel - Profile on Academia.edu (original) (raw)
Papers by Jerrold Heindel
Assessment of the Reproductive Toxicity of a Complex Mixture of 25 Groundwater Contaminants in Mice and Rats 1
Toxicological Sciences, 1995
The potential reproductive toxicity of a mixture of 25 chemicals (MIX) formulated to simulate con... more The potential reproductive toxicity of a mixture of 25 chemicals (MIX) formulated to simulate contaminated groundwater supplies near hazardous waste dumps was evaluated in CD-1 Swiss mice and Sprague-Dawley rats using the reproductive assessment by continuous breeding protocol. Male and female mice and rats were exposed to MIX in the drinking water at concentrations of 1, 5, and 10% of a technically achievable stock solution. For mice, body weight and feed consumption were not affected by MIX but water consumption was decreased for both the 5 and 10% MIX groups in both F0 and F1 animals. For F0 mice, the number of live pups/litter was decreased at 10% MIX and the number of females/litter was decreased 10 and 17% at the mid and high MIX dose, respectively. Vaginal cytology was normal, as were testis weight and testicular spermatid head count. For F1 mice, fertility was unaffected, but there was a decreased number of female pups/litter (19%) and a decreased adjusted live pup weight at 10% MIX. At necropsy, cauda epididymal sperm concentration and spermatid head count were reduced (20%) in the presence of normal testis, epididymis, prostate, seminal vesicle, liver, and kidney/adrenal weight. Female estrous cyclicity was altered at 5 and 10% MIX with normal kidney/adrenal, uterus, and ovary/oviduct weight. For rats, F0 body weight and feed consumption were not affected by MIX but water consumption was decreased 10, 30, and 40% in the low-, medium-, and high-dose MIX groups, respectively, and 39% in the high-dose MIX F1 animals. Rat fertility was normal but there was a decreased number of male pups/litter (11%) and a decreased live pup weight (6%) at 10% MIX. Male and female (F1) pup weights were decreased on Postnatal Days 0, 4, 7, 14, and 21 (10% MIX) and remained lower through necropsy on Day 120 +/- 10. F1 fertility was normal but F2 pup weights were decreased (10% MIX). At necropsy, F1 (10% MIX) male body weight was decreased 16% and relative kidney, testis, epididymis, and prostate weights were increased in the presence of normal sperm concentration percentage motile sperm and percentage abnormal sperm. Estrous cyclicity was normal as were kidney/adrenal and ovary weight while female liver weight was reduced 14%. In summary, a "cocktail" of 25 chemicals commonly found in contaminated groundwater at or near hazardous waste sites was administered in drinking water at doses which resulted in severely decreased water consumption in both mice and rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Carisoprodol: Reproductive Assessment by Continuous Breeding in Swiss Mice
Toxicological Sciences, 1995
Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant, was evaluated for reproductive... more Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant, was evaluated for reproductive toxicity in Swiss CD-1 mice using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Male and female mice were given CARI in corn oil suspension by daily gavage at doses of 0, 300, 750, and 1200 mg/kg body wt/day. Clinical signs of general toxicity in F0 animals included sedation, primarily in the high-dose group during the first week of exposure, and reduced body weight in high-dose females. CARI administration for 14 weeks did not affect the ability of the F0 animals to produce litters. However, decreases in proportion of pups born alive (4%) and absolute (5%) and adjusted live pup weight (7%) were observed at 1200 mg/kg CARI when compared to controls. In a crossover mating trial to determine the affected sex, there were no significant differences in the measured reproductive parameters. CARI at the high dose increased the proportion of time spent in proestrus and estrus, but cycle length was unaffected. At F0 necropsy (Week 27 of treatment), all sperm parameters were normal. Right epididymis and liver weights, relative to body weight, were increased (12 and 23%, respectively) over the control group for high-dose males. A mating trial to determine the fertility and reproductive competence of the F1 generation showed no effect of CARI on indices of mating, pregnancy, or fertility, the proportion of F2 pups born alive, the sex ratio of live F2 pups, live F2 pup weight, or gestation length.(ABSTRACT TRUNCATED AT 250 WORDS)
Assessment of the Reproductive and Developmental Toxicity of Pesticide/Fertilizer Mixtures Based on Confirmed Pesticide Contamination in California and Iowa Groundwater
Toxicological Sciences, 1994
Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level co... more Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level contamination of groundwater sources. In order to determine the potential of pesticide and fertilizer mixtures to produce reproductive or developmental toxicity at concentrations up to 100 x the median level found in groundwater, we prepared and studied two mixtures of pesticides and a fertilizer (ammonium nitrate). One mixture containing aldicarb, atrazine, dibromochloropropane, 1,2-dichloropropane, ethylene dibromide, and simazine plus ammonium nitrate was considered to be a representative of groundwater contamination in California (CAL). The other, containing alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate, simulated groundwater contamination in Iowa (IOWA). Each mixture was administered in the drinking water of either Swiss CD-1 mice during a Reproductive Assessment by Continuous Breeding study or pregnant Sprague-Dawley rats (gd 6-20) at three dose levels (1x, 10x, and 100x) where 1x was the median concentration of each pesticide component as determined in the groundwater surveys in California or Iowa. Unlike conventional toxicology studies, the purpose of this study was to evaluate the health effects of realistic human concentrations. Thus, the testing concentrations are probably well below the maximally tolerated dose. Propylene glycol was used as the solubilizer for the pesticides in drinking water formulations in both studies. In the reproductive study, neither mixture caused any clinical signs of toxicity, changes in food or water consumption, or body weight in either F0 or F1 mice at doses up to 100x the median groundwater concentrations. There were no treatment-related effects on fertility or any measures of reproductive performance of either the F0 or the F1 generation mice exposed to either CAL or IOWA at up to 100x. Similarly, measures of spermatogenesis, epididymal sperm concentration, percentage motile sperm, percentage abnormal sperm, and testicular and epididymal histology were normal. In the developmental study, CAL- or IOWA-exposed females did not exhibit any significant treatment-related clinical signs of toxicity. No adverse effects of CAL or IOWA were observed for measures of embryo/fetal toxicity, including resorptions per litter, live litter size, or fetal body weight. CAL or IOWA did not cause an increased incidence of fetal malformations or variations. In summary, administration of these pesticide/fertilizer mixtures at levels up to 100-fold greater than the median concentrations in groundwater supplies in California or Iowa did not cause any detectable reproductive (mice), general, or developmental toxicity (rats).
Evaluation of the Developmental Toxicity of Methacrylonitrile in Sprague-Dawley Rats and New Zealand White Rabbits
Toxicological Sciences, 1996
Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavag... more Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavage with methacrylonitrile (MACR) in distilled water during major organogenesis. Rats were dosed on Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day) and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day). Maternal clinical status was monitored daily during treatment. At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnant females (25-26 per group, rats; 17-22 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In rats, no treatment-related maternal clinical signs or mortality were observed, nor was there any adverse effect on maternal body weight or food or water consumption. At necropsy, absolute, relative, and adjusted maternal liver weight was increased at the mid- and high-dose groups, an effect that may be indicative of induction of hepatic enzymes rather than toxicity. In the absence of any indication of maternal toxicity, the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study was >/=50 mg MACR/kg/day. The NOAEL for developmental toxicity in rats was also >/=50 mg MACR/kg/day. There was no effect of treatment on postimplantation loss, mean fetal body weight per litter, or morphological development. In rabbits, maternal mortality and clinical signs were not dose related. Maternal food consumption, body weight, and liver weight were not adversely affected by treatment. Thus, the maternal NOAEL was >/=5 mg MACR/kg/day. Maternal toxicity, including death, was observed >/=7.5 mg/kg/day in preliminary studies. The developmental NOAEL was also >/=5 mg MACR/kg/day. There was no adverse effect of treatment on postimplantation loss or fetal body weight. A significant decrease in the percentage male fetuses per litter was observed, although there was no effect on total live litter size, suggesting that the reduction in the ratio of live male fetuses in the high-dose group was not biologically significant. MACR had no adverse effect on morphological development. In summary, oral administration of MACR to rats and rabbits during organogenesis, at doses that did not cause persistent maternal toxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits), also did not cause any adverse developmental effects.
Toxicological Sciences, 1994
Toxicological Sciences, 1996
Nitrofurazone (NTFZ), a nitrofuran antibiotic, was evaluated for reproductive toxicity in Swiss C... more Nitrofurazone (NTFZ), a nitrofuran antibiotic, was evaluated for reproductive toxicity in Swiss CD-I mice using the Reproductive Assessment by Continuous Breeding protocol. Male and female mice were cohabited for 15 weeks and exposed to NTFZ in feed at concentrations of 0, 100, 375, and 750 ppm (14-102 mg/kg/day). F o 750-ppm breeding pairs had significantly reduced fertility after 7 days of exposure to NTFZ (17% fertile compared to 98% for control pairs) and were infertile after the second litter. F o mid-dose pairs had progressively decreasing fertility (47% by the fifth litter), reduced litter size, and reduced proportion of pups born alive. Crossover breeding of control and high-dose F o animals confirmed infertility in high-dose males and reduced litter size and pup weight in high-dose females when compared to the control x control group. At necropsy, there were no effects on body weight, but F o males had reduced testis weight at the high dose and reduced epididymal sperm concentration and abnormal sperm morphology at all doses of NTFZ. Increased liver as well as kidney and adrenal weights (combined) were observed at 375 and 750 ppm; hepatic hypertrophy was noted microscopically at 750 ppm. F o females had reduced body weight, hepatic hypertrophy, and altered estrous cycles at 750 ppm and reduced ovarian weight at all doses. In the second generation, F, mice at 375 ppm had reduced postnatal survival and body weight and produced smaller F 2 litters compared to control mice. At necropsy, F, males had reduced testes weight and epididymal sperm concentration, abnormal sperm morphology, hepatic hypertrophy at 375 ppm, and borderline nephropathy at 100 and 375 ppm. F, females had decreased body, liver, and ovarian weight at 375 ppm and altered estrous cycles at 100 and 375 ppm. Thus, NTFZ at ;»100 ppm (=*14 mg/kg/day) caused adverse reproductive effects in F o male and female and F, female mice in the presence of relatively mild systemic toxicity. © 19% sodoy of Toiiccioiy.
Reproductive Toxicity of Boric Acid in Swiss (CD-1) Mice: Assessment Using the Continuous Breeding Protocol
Toxicological Sciences, 1991
The potential reproductive toxicity of boric acid (BORA) in CD-1 mice (Swiss) was evaluated using... more The potential reproductive toxicity of boric acid (BORA) in CD-1 mice (Swiss) was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. BORA was administered in the feed for 27 weeks to male and female Swiss (CD-1) mice at concentrations of 0, 1000, 4500, or 9000 ppm. Estimated doses, based on feed consumption and body weight, averaged 152, 636, and 1262 mg/kg body wt during Week 1 for males for 1000, 4500, and 9000 ppm, respectively. During 14 weeks of cohabitation, fertility of F0 mice was partially reduced at 4500 ppm and totally eliminated at 9000 ppm. No litters, dead or alive, were produced by 9000 ppm cohabited pairs. Among the litters born at 4500 ppm, live litter size and body weight were significantly reduced. A crossover mating trial of control and 4500 ppm groups confirmed the male as the affected sex, with fertility rates and the mating index significantly lower in the 4500 male x 0 ppm female group. At necropsy, after 27 weeks of BORA exposure, dose-related changes were present in F0 males for reduced body and reproductive organ weights, increased incidence of abnormal sperm, decreased sperm concentration and motility, and seminiferous tubule degeneration. In the 4500 ppm females, dietary BORA for 27 weeks caused significantly decreased weights of kidney/adrenals and livers; kidney/adrenal weight was also reduced in 4500 ppm males. The last litters of the control and 1000 ppm females, born in the 14-week breeding phase, were reared to 74 days of age and then mated in nonsibling pairs within treatment groups. These F1 mice had normal fertility, but the adjusted mean body weight of F2 pups was decreased. These data establish the reproductive toxicity of BORA in CD-1 mice and demonstrate that the male is the most sensitive sex.
Toxicological Sciences, 1993
Although it is known that severe feed restriction (FR) and weight reduction (to 50-60% of control... more Although it is known that severe feed restriction (FR) and weight reduction (to 50-60% of control values) will sharply impair rat reproduction, few data exist on the effects of less severe body weight reduction. In the present studies, adult Sprague-Dawley rats were feed restricted and maintained at 90, 80, and 70% of control body weight (CBW) for up to 17 weeks. In females, this treatment had no effect on fertility or total number of implants per dam, but transiently increased the length of the estrous cycle and decreased by 20% the number of corpora lutea in the 70% CBW females. Ovary weight at necropsy was decreased only in the 70% CBW group. Liver and kidney weights varied with body weight. In males, fertility was not affected when they were mated to nonrestricted females. While prostate and seminal vesicles weight varied with body weight, testis and epididymis weights were unchanged by any degree of FR, as were the number of sperm in the cauda epididymis and the number of homogenization-resistant spermatids in the testis. The percentage motile sperm was slightly decreased at all levels of FR. These data show that the Sprague-Dawley rat is largely resistant to adverse reproductive changes caused by feed restriction to 70% CBW. These data should be of use in interpreting changes seen in toxicity studies that produce weight-reduced Sprague-Dawley ratS. © 1993 Society of Toxicology.
Reproductive Toxicology, 1998
Reproductive toxicity in Swiss mice, during chronic exposure to formamide (FORM) or dimethylforma... more Reproductive toxicity in Swiss mice, during chronic exposure to formamide (FORM) or dimethylformamide (DMF), was evaluated using the Reproductive Assessment by Continuous Breeding Protocols. FORM administered in drinking water at 0, 100, 350, and 750 ppm (ϳ20 to 200 mg/kg/d) reduced fertility and litter size in F 0 animals without generalized toxicity at 750 ppm FORM. Crossover matings suggested that females were the affected sex. After F 1 mating, FORM reduced F 2 litter size, increased days to litter, reduced relative ovarian weight, and lengthened estrous cycles at 750 ppm. The No-Observed-Adverse-Effect-Level for generalized toxicity was 750 ppm for the F 0 and 350 ppm for the F 1 generation. Reproductive performance was normal at 350 ppm for both F 0 and F 1 mice. Chronic exposure to DMF in drinking water at 0, 1000, 4000, and 7000 ppm (ϳ200 to 1300 mg/kg/d) reduced fertility by the first litter at 4000 ppm, reduced body weight in F 0 females at 7000 ppm, and increased liver weights at all doses in both sexes. A crossover mating at 7000 ppm identified F 0 females as the affected sex. F 1 postnatal survival was reduced at >4000 ppm DMF. F 1 mating reduced F 2 litter size and live pup weight at >1000 ppm. At necropsy, body weight of F 1 males and females was reduced at >4000 ppm. DMF-treated pups (both F l and F 2 ) and F l adults had cranial and sternebral skeletal malformations. Only DMF caused overt developmental toxicity. A No-Observed-Adverse-Effect-Level for DMF was not established. © 1998 Elsevier Science Inc.
Fundamental and Applied Toxicology Official Journal of the Society of Toxicology, Aug 1, 1995
THE DIABETES EPIDEMIC: Environmental Chemical Exposure in Etiology and Treatment
Endocrine Disruption for Endocrinologists (and Others)
Endocrinology, Jul 1, 2013
Cell associated nonesterified fatty acid levels and their alteration during lipolysis in the isolated mouse adipose cell
The Journal of Lipid Research
A rapid and flexible method has been developed for measuring cell-associated, probably intracellu... more A rapid and flexible method has been developed for measuring cell-associated, probably intracellular, nonesterified fatty acids (CAFA) in isolated mouse adipose cells. A variety of lipolytic agents as well as various concentrations of epinephrine elevate CAFA levels in rough proportion to their stimulation of glycerol and fatty acid release. Insulin reduces epinephrine-elevated CAFA levels. A detailed, quantitative study of the relationship among lipolytic activity, CAFA levels, and the extracellular molar ratio of fatty acids to albumin has been carried out. Epinephrine-elevated CAFA levels rise linearly with, while epinephrine-stimulated lipolytic activity is independent of, fatty acid to albumin ratios below 2-3. As the ratio increases from 3 to 5, CAFA levels continue to increase, whereas lipolytic activity decreases. Above ratios of 5, fatty acid release almost completely ceases; CAFA levels increase dramatically with residual glycerol release. A temperature-dependent efflux of epinephrine-elevated CAFA can be elicited through blockade of stimulated lipolysis with propranolol, but only in the presence of extracellular fatty acid to albumin ratios below 3. These observations suggest that during stimulated lipolysis, a fatty acid gradient exists between the cell and extracellular serum albumin and that CAFA represent the intracellular component of this gradient. In addition, these observations support the concept that intracellular fatty acids play a role in the feedback regulation of adipose cell function as extracellular fatty acids accumulate during the lipolytic response.
Cell-associated fatty acid levels and energy requiring process in mouse adipocyte
The American journal of physiology
ABSTRACT
Fundamental and Applied Toxicology
. Fundam. Appl. Toxicol. 13,. This investigation was undertaken to assess the potential of ingest... more . Fundam. Appl. Toxicol. 13,. This investigation was undertaken to assess the potential of ingested 1,2-dibromo-3-chloropropane (DBCP) to cause testicular and hepatorenal injury, in Iight of the paucity of data applicable to risk assessment of DBCP in drinking water. Adult male Sprague-Dawley rats were supplied ad libitum with water containing 0, 5, 50, 100, and 200 ppm DBCP for 64 days. A dose-related decrease in water consumption occurred during the study. The 200-ppm animals drank less than half as much water as controls, consumed less food, and subsequently exhibited significantly lower body weight gain. DBCP ingestion thus was not directly proportional to the level of chemical in the water, although daily and cumulative intake of DCP were concentration dependent. Average daily intake of DBCP for the 6Cday exposure period was as follows: 5 ppm = 0.4 m&kg/day; 50 ppm = 3.3 m&kg/day; 100 ppm = 5.4 mg/kg/day; 200 ppm = 9.7 mg&/day. Blood samples were taken after 2,4, and 6 weeks of exposure and at the terminal sacrifice and assayed for serum glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, sorbit dehydrogenase, and omithine-carbamyl transferase activities and BUN levels. No evidence of liver damage at any exposure level was indicated by either the clinical chemistry indices or histopathology. Histologic examination revealed an apparent increase in the number of nuclei per renal proximal tubule cross-section in the 200-ppm group, possibly indicative of an increased turnover of proximal tubular cells. A slight, but statistically significant, decrease in absolute testicular weight was manifest in the 200-ppm animals, although the decrease was not significant when testicular weight was calculated as g/ 100 g body wt. Epididymal sperm counts and serum luteinizing hormone, follicle stimulating hormone, and intratesticular testosterone levels were not altered by any dose of DBCP. A qualitative histopatholc&aI examina tion of the testicular seminiferous epithelium failed to reveal any abnormalities in the SpennatogenC process. 8 1989 sociay of Tmicdqy ' Supported in part by NIEHS Training Grant ES07090.
Endocrine disruptors and obesity
Nature reviews. Endocrinology, 2015
The increasing incidence of obesity is a serious global public health challenge. Although the obe... more The increasing incidence of obesity is a serious global public health challenge. Although the obesity epidemic is largely fueled by poor nutrition and lack of exercise, certain chemicals have been shown to potentially have a role in its aetiology. A substantial body of evidence suggests that a subclass of endocrine-disrupting chemicals (EDCs), which interfere with endocrine signalling, can disrupt hormonally regulated metabolic processes, especially if exposure occurs during early development. These chemicals, so-called 'obesogens' might predispose some individuals to gain weight despite their efforts to limit caloric intake and increase levels of physical activity. This Review discusses the role of EDCs in the obesity epidemic, the latest research on the obesogen concept, epidemiological and experimental findings on obesogens, and their modes of action. The research reviewed here provides knowledge that health scientists can use to inform their research and decision-making ...
Developmental Origins of Health and Disease: Integrating Environmental Influences
Endocrinology, Jan 4, 2015
There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) para... more There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) paradigm. This includes human and animal data focusing on nutrition or environmental chemicals during development. However, the term DOHaD has not been generally accepted as the official term to be used when one is concerned with understanding the pathophysiological basis for how environmental influences acting during early development influence the risk of later noncommunicable diseases. Similarly, there is no global research or public health program built around the DOHaD paradigm that encompasses all aspects of environment. To better inform the global health efforts aimed at addressing the growing epidemic of chronic noncommunicable diseases of environmental origin, we propose a two-pronged approach: first, to make it clear that the current concept of DOHaD comprehensively includes a range of environmental factors and their relevance to disease occurrence not just throughout the life span...
Current Environmental Health Reports, 2014
Obesity and diabetes have overtaken smoking as the number 1 preventable health determinate in the... more Obesity and diabetes have overtaken smoking as the number 1 preventable health determinate in the United States. In its basic form, obesity is due to disruptions of the endocrine systems that control food intake, satiety, and metabolic rate. Recent studies have identified a subclass of endocrine disrupting chemicals that interfere with hormonally regulated metabolic processes, especially during early development. These chemicals, called "obesogens," may predispose individuals to gain weight despite efforts to limit caloric intake and increase physical activity. Evidence suggests that chemical exposures early in life can predispose individuals to weight gain through programming changes, which may enhance dysfunctional eating behaviors later in life. This review examines the latest research on the obesogen hypothesis and its underpinnings in the Developmental Origins of Heath and Disease model. We provide examples of known and suspected obesogens, and evidence of their general mechanisms of action. The research reviewed here provides a solid foundation of knowledge from which health scientists may draw from and build upon to inform their research and decision-making.
Reproductive Toxicology, 2015
Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in... more Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in potential daily human exposure to this chemical. The FDA previously evaluated the toxicity of BPA and determined that it is safe at current exposure levels. This determination of BPA safety is not consistent with a body of literature from hypothesis driven studies and its safety continues to be debated in scientific and popular publications. Thus, the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively a variety of hypothesis-based research investigations and guidelinecompliant safety testing with BPA. This collaboration is known as the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). This paper provides a detailed description of the conduct of the study and a midterm update on progress of the CLARITY-BPA research program.
Endocrinology, Jan 4, 2015
The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expan... more The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expanding areas of biomedical research. Environmental stressors that can impact on DOHaD encompass a variety of environmental and occupational hazards as well as deficiency and oversupply of nutrients and energy. They can disrupt early developmental processes and lead to increased susceptibility to disease/dysfunctions later in life. Presentations at the fourth Conference on Prenatal Programming and Toxicity in Boston, in October 2014, provided important insights and led to new recommendations for research and public health action. The conference highlighted vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous "reprogramming" of the genome, thereby potentially resulting in transgenerational effects. Stem cells can also be targets of environmental stressors, thus paving another way for ef...
Assessment of the Reproductive Toxicity of a Complex Mixture of 25 Groundwater Contaminants in Mice and Rats 1
Toxicological Sciences, 1995
The potential reproductive toxicity of a mixture of 25 chemicals (MIX) formulated to simulate con... more The potential reproductive toxicity of a mixture of 25 chemicals (MIX) formulated to simulate contaminated groundwater supplies near hazardous waste dumps was evaluated in CD-1 Swiss mice and Sprague-Dawley rats using the reproductive assessment by continuous breeding protocol. Male and female mice and rats were exposed to MIX in the drinking water at concentrations of 1, 5, and 10% of a technically achievable stock solution. For mice, body weight and feed consumption were not affected by MIX but water consumption was decreased for both the 5 and 10% MIX groups in both F0 and F1 animals. For F0 mice, the number of live pups/litter was decreased at 10% MIX and the number of females/litter was decreased 10 and 17% at the mid and high MIX dose, respectively. Vaginal cytology was normal, as were testis weight and testicular spermatid head count. For F1 mice, fertility was unaffected, but there was a decreased number of female pups/litter (19%) and a decreased adjusted live pup weight at 10% MIX. At necropsy, cauda epididymal sperm concentration and spermatid head count were reduced (20%) in the presence of normal testis, epididymis, prostate, seminal vesicle, liver, and kidney/adrenal weight. Female estrous cyclicity was altered at 5 and 10% MIX with normal kidney/adrenal, uterus, and ovary/oviduct weight. For rats, F0 body weight and feed consumption were not affected by MIX but water consumption was decreased 10, 30, and 40% in the low-, medium-, and high-dose MIX groups, respectively, and 39% in the high-dose MIX F1 animals. Rat fertility was normal but there was a decreased number of male pups/litter (11%) and a decreased live pup weight (6%) at 10% MIX. Male and female (F1) pup weights were decreased on Postnatal Days 0, 4, 7, 14, and 21 (10% MIX) and remained lower through necropsy on Day 120 +/- 10. F1 fertility was normal but F2 pup weights were decreased (10% MIX). At necropsy, F1 (10% MIX) male body weight was decreased 16% and relative kidney, testis, epididymis, and prostate weights were increased in the presence of normal sperm concentration percentage motile sperm and percentage abnormal sperm. Estrous cyclicity was normal as were kidney/adrenal and ovary weight while female liver weight was reduced 14%. In summary, a "cocktail" of 25 chemicals commonly found in contaminated groundwater at or near hazardous waste sites was administered in drinking water at doses which resulted in severely decreased water consumption in both mice and rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Carisoprodol: Reproductive Assessment by Continuous Breeding in Swiss Mice
Toxicological Sciences, 1995
Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant, was evaluated for reproductive... more Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant, was evaluated for reproductive toxicity in Swiss CD-1 mice using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Male and female mice were given CARI in corn oil suspension by daily gavage at doses of 0, 300, 750, and 1200 mg/kg body wt/day. Clinical signs of general toxicity in F0 animals included sedation, primarily in the high-dose group during the first week of exposure, and reduced body weight in high-dose females. CARI administration for 14 weeks did not affect the ability of the F0 animals to produce litters. However, decreases in proportion of pups born alive (4%) and absolute (5%) and adjusted live pup weight (7%) were observed at 1200 mg/kg CARI when compared to controls. In a crossover mating trial to determine the affected sex, there were no significant differences in the measured reproductive parameters. CARI at the high dose increased the proportion of time spent in proestrus and estrus, but cycle length was unaffected. At F0 necropsy (Week 27 of treatment), all sperm parameters were normal. Right epididymis and liver weights, relative to body weight, were increased (12 and 23%, respectively) over the control group for high-dose males. A mating trial to determine the fertility and reproductive competence of the F1 generation showed no effect of CARI on indices of mating, pregnancy, or fertility, the proportion of F2 pups born alive, the sex ratio of live F2 pups, live F2 pup weight, or gestation length.(ABSTRACT TRUNCATED AT 250 WORDS)
Assessment of the Reproductive and Developmental Toxicity of Pesticide/Fertilizer Mixtures Based on Confirmed Pesticide Contamination in California and Iowa Groundwater
Toxicological Sciences, 1994
Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level co... more Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level contamination of groundwater sources. In order to determine the potential of pesticide and fertilizer mixtures to produce reproductive or developmental toxicity at concentrations up to 100 x the median level found in groundwater, we prepared and studied two mixtures of pesticides and a fertilizer (ammonium nitrate). One mixture containing aldicarb, atrazine, dibromochloropropane, 1,2-dichloropropane, ethylene dibromide, and simazine plus ammonium nitrate was considered to be a representative of groundwater contamination in California (CAL). The other, containing alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate, simulated groundwater contamination in Iowa (IOWA). Each mixture was administered in the drinking water of either Swiss CD-1 mice during a Reproductive Assessment by Continuous Breeding study or pregnant Sprague-Dawley rats (gd 6-20) at three dose levels (1x, 10x, and 100x) where 1x was the median concentration of each pesticide component as determined in the groundwater surveys in California or Iowa. Unlike conventional toxicology studies, the purpose of this study was to evaluate the health effects of realistic human concentrations. Thus, the testing concentrations are probably well below the maximally tolerated dose. Propylene glycol was used as the solubilizer for the pesticides in drinking water formulations in both studies. In the reproductive study, neither mixture caused any clinical signs of toxicity, changes in food or water consumption, or body weight in either F0 or F1 mice at doses up to 100x the median groundwater concentrations. There were no treatment-related effects on fertility or any measures of reproductive performance of either the F0 or the F1 generation mice exposed to either CAL or IOWA at up to 100x. Similarly, measures of spermatogenesis, epididymal sperm concentration, percentage motile sperm, percentage abnormal sperm, and testicular and epididymal histology were normal. In the developmental study, CAL- or IOWA-exposed females did not exhibit any significant treatment-related clinical signs of toxicity. No adverse effects of CAL or IOWA were observed for measures of embryo/fetal toxicity, including resorptions per litter, live litter size, or fetal body weight. CAL or IOWA did not cause an increased incidence of fetal malformations or variations. In summary, administration of these pesticide/fertilizer mixtures at levels up to 100-fold greater than the median concentrations in groundwater supplies in California or Iowa did not cause any detectable reproductive (mice), general, or developmental toxicity (rats).
Evaluation of the Developmental Toxicity of Methacrylonitrile in Sprague-Dawley Rats and New Zealand White Rabbits
Toxicological Sciences, 1996
Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavag... more Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavage with methacrylonitrile (MACR) in distilled water during major organogenesis. Rats were dosed on Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day) and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day). Maternal clinical status was monitored daily during treatment. At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnant females (25-26 per group, rats; 17-22 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In rats, no treatment-related maternal clinical signs or mortality were observed, nor was there any adverse effect on maternal body weight or food or water consumption. At necropsy, absolute, relative, and adjusted maternal liver weight was increased at the mid- and high-dose groups, an effect that may be indicative of induction of hepatic enzymes rather than toxicity. In the absence of any indication of maternal toxicity, the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study was >/=50 mg MACR/kg/day. The NOAEL for developmental toxicity in rats was also >/=50 mg MACR/kg/day. There was no effect of treatment on postimplantation loss, mean fetal body weight per litter, or morphological development. In rabbits, maternal mortality and clinical signs were not dose related. Maternal food consumption, body weight, and liver weight were not adversely affected by treatment. Thus, the maternal NOAEL was >/=5 mg MACR/kg/day. Maternal toxicity, including death, was observed >/=7.5 mg/kg/day in preliminary studies. The developmental NOAEL was also >/=5 mg MACR/kg/day. There was no adverse effect of treatment on postimplantation loss or fetal body weight. A significant decrease in the percentage male fetuses per litter was observed, although there was no effect on total live litter size, suggesting that the reduction in the ratio of live male fetuses in the high-dose group was not biologically significant. MACR had no adverse effect on morphological development. In summary, oral administration of MACR to rats and rabbits during organogenesis, at doses that did not cause persistent maternal toxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits), also did not cause any adverse developmental effects.
Toxicological Sciences, 1994
Toxicological Sciences, 1996
Nitrofurazone (NTFZ), a nitrofuran antibiotic, was evaluated for reproductive toxicity in Swiss C... more Nitrofurazone (NTFZ), a nitrofuran antibiotic, was evaluated for reproductive toxicity in Swiss CD-I mice using the Reproductive Assessment by Continuous Breeding protocol. Male and female mice were cohabited for 15 weeks and exposed to NTFZ in feed at concentrations of 0, 100, 375, and 750 ppm (14-102 mg/kg/day). F o 750-ppm breeding pairs had significantly reduced fertility after 7 days of exposure to NTFZ (17% fertile compared to 98% for control pairs) and were infertile after the second litter. F o mid-dose pairs had progressively decreasing fertility (47% by the fifth litter), reduced litter size, and reduced proportion of pups born alive. Crossover breeding of control and high-dose F o animals confirmed infertility in high-dose males and reduced litter size and pup weight in high-dose females when compared to the control x control group. At necropsy, there were no effects on body weight, but F o males had reduced testis weight at the high dose and reduced epididymal sperm concentration and abnormal sperm morphology at all doses of NTFZ. Increased liver as well as kidney and adrenal weights (combined) were observed at 375 and 750 ppm; hepatic hypertrophy was noted microscopically at 750 ppm. F o females had reduced body weight, hepatic hypertrophy, and altered estrous cycles at 750 ppm and reduced ovarian weight at all doses. In the second generation, F, mice at 375 ppm had reduced postnatal survival and body weight and produced smaller F 2 litters compared to control mice. At necropsy, F, males had reduced testes weight and epididymal sperm concentration, abnormal sperm morphology, hepatic hypertrophy at 375 ppm, and borderline nephropathy at 100 and 375 ppm. F, females had decreased body, liver, and ovarian weight at 375 ppm and altered estrous cycles at 100 and 375 ppm. Thus, NTFZ at ;»100 ppm (=*14 mg/kg/day) caused adverse reproductive effects in F o male and female and F, female mice in the presence of relatively mild systemic toxicity. © 19% sodoy of Toiiccioiy.
Reproductive Toxicity of Boric Acid in Swiss (CD-1) Mice: Assessment Using the Continuous Breeding Protocol
Toxicological Sciences, 1991
The potential reproductive toxicity of boric acid (BORA) in CD-1 mice (Swiss) was evaluated using... more The potential reproductive toxicity of boric acid (BORA) in CD-1 mice (Swiss) was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. BORA was administered in the feed for 27 weeks to male and female Swiss (CD-1) mice at concentrations of 0, 1000, 4500, or 9000 ppm. Estimated doses, based on feed consumption and body weight, averaged 152, 636, and 1262 mg/kg body wt during Week 1 for males for 1000, 4500, and 9000 ppm, respectively. During 14 weeks of cohabitation, fertility of F0 mice was partially reduced at 4500 ppm and totally eliminated at 9000 ppm. No litters, dead or alive, were produced by 9000 ppm cohabited pairs. Among the litters born at 4500 ppm, live litter size and body weight were significantly reduced. A crossover mating trial of control and 4500 ppm groups confirmed the male as the affected sex, with fertility rates and the mating index significantly lower in the 4500 male x 0 ppm female group. At necropsy, after 27 weeks of BORA exposure, dose-related changes were present in F0 males for reduced body and reproductive organ weights, increased incidence of abnormal sperm, decreased sperm concentration and motility, and seminiferous tubule degeneration. In the 4500 ppm females, dietary BORA for 27 weeks caused significantly decreased weights of kidney/adrenals and livers; kidney/adrenal weight was also reduced in 4500 ppm males. The last litters of the control and 1000 ppm females, born in the 14-week breeding phase, were reared to 74 days of age and then mated in nonsibling pairs within treatment groups. These F1 mice had normal fertility, but the adjusted mean body weight of F2 pups was decreased. These data establish the reproductive toxicity of BORA in CD-1 mice and demonstrate that the male is the most sensitive sex.
Toxicological Sciences, 1993
Although it is known that severe feed restriction (FR) and weight reduction (to 50-60% of control... more Although it is known that severe feed restriction (FR) and weight reduction (to 50-60% of control values) will sharply impair rat reproduction, few data exist on the effects of less severe body weight reduction. In the present studies, adult Sprague-Dawley rats were feed restricted and maintained at 90, 80, and 70% of control body weight (CBW) for up to 17 weeks. In females, this treatment had no effect on fertility or total number of implants per dam, but transiently increased the length of the estrous cycle and decreased by 20% the number of corpora lutea in the 70% CBW females. Ovary weight at necropsy was decreased only in the 70% CBW group. Liver and kidney weights varied with body weight. In males, fertility was not affected when they were mated to nonrestricted females. While prostate and seminal vesicles weight varied with body weight, testis and epididymis weights were unchanged by any degree of FR, as were the number of sperm in the cauda epididymis and the number of homogenization-resistant spermatids in the testis. The percentage motile sperm was slightly decreased at all levels of FR. These data show that the Sprague-Dawley rat is largely resistant to adverse reproductive changes caused by feed restriction to 70% CBW. These data should be of use in interpreting changes seen in toxicity studies that produce weight-reduced Sprague-Dawley ratS. © 1993 Society of Toxicology.
Reproductive Toxicology, 1998
Reproductive toxicity in Swiss mice, during chronic exposure to formamide (FORM) or dimethylforma... more Reproductive toxicity in Swiss mice, during chronic exposure to formamide (FORM) or dimethylformamide (DMF), was evaluated using the Reproductive Assessment by Continuous Breeding Protocols. FORM administered in drinking water at 0, 100, 350, and 750 ppm (ϳ20 to 200 mg/kg/d) reduced fertility and litter size in F 0 animals without generalized toxicity at 750 ppm FORM. Crossover matings suggested that females were the affected sex. After F 1 mating, FORM reduced F 2 litter size, increased days to litter, reduced relative ovarian weight, and lengthened estrous cycles at 750 ppm. The No-Observed-Adverse-Effect-Level for generalized toxicity was 750 ppm for the F 0 and 350 ppm for the F 1 generation. Reproductive performance was normal at 350 ppm for both F 0 and F 1 mice. Chronic exposure to DMF in drinking water at 0, 1000, 4000, and 7000 ppm (ϳ200 to 1300 mg/kg/d) reduced fertility by the first litter at 4000 ppm, reduced body weight in F 0 females at 7000 ppm, and increased liver weights at all doses in both sexes. A crossover mating at 7000 ppm identified F 0 females as the affected sex. F 1 postnatal survival was reduced at >4000 ppm DMF. F 1 mating reduced F 2 litter size and live pup weight at >1000 ppm. At necropsy, body weight of F 1 males and females was reduced at >4000 ppm. DMF-treated pups (both F l and F 2 ) and F l adults had cranial and sternebral skeletal malformations. Only DMF caused overt developmental toxicity. A No-Observed-Adverse-Effect-Level for DMF was not established. © 1998 Elsevier Science Inc.
Fundamental and Applied Toxicology Official Journal of the Society of Toxicology, Aug 1, 1995
THE DIABETES EPIDEMIC: Environmental Chemical Exposure in Etiology and Treatment
Endocrine Disruption for Endocrinologists (and Others)
Endocrinology, Jul 1, 2013
Cell associated nonesterified fatty acid levels and their alteration during lipolysis in the isolated mouse adipose cell
The Journal of Lipid Research
A rapid and flexible method has been developed for measuring cell-associated, probably intracellu... more A rapid and flexible method has been developed for measuring cell-associated, probably intracellular, nonesterified fatty acids (CAFA) in isolated mouse adipose cells. A variety of lipolytic agents as well as various concentrations of epinephrine elevate CAFA levels in rough proportion to their stimulation of glycerol and fatty acid release. Insulin reduces epinephrine-elevated CAFA levels. A detailed, quantitative study of the relationship among lipolytic activity, CAFA levels, and the extracellular molar ratio of fatty acids to albumin has been carried out. Epinephrine-elevated CAFA levels rise linearly with, while epinephrine-stimulated lipolytic activity is independent of, fatty acid to albumin ratios below 2-3. As the ratio increases from 3 to 5, CAFA levels continue to increase, whereas lipolytic activity decreases. Above ratios of 5, fatty acid release almost completely ceases; CAFA levels increase dramatically with residual glycerol release. A temperature-dependent efflux of epinephrine-elevated CAFA can be elicited through blockade of stimulated lipolysis with propranolol, but only in the presence of extracellular fatty acid to albumin ratios below 3. These observations suggest that during stimulated lipolysis, a fatty acid gradient exists between the cell and extracellular serum albumin and that CAFA represent the intracellular component of this gradient. In addition, these observations support the concept that intracellular fatty acids play a role in the feedback regulation of adipose cell function as extracellular fatty acids accumulate during the lipolytic response.
Cell-associated fatty acid levels and energy requiring process in mouse adipocyte
The American journal of physiology
ABSTRACT
Fundamental and Applied Toxicology
. Fundam. Appl. Toxicol. 13,. This investigation was undertaken to assess the potential of ingest... more . Fundam. Appl. Toxicol. 13,. This investigation was undertaken to assess the potential of ingested 1,2-dibromo-3-chloropropane (DBCP) to cause testicular and hepatorenal injury, in Iight of the paucity of data applicable to risk assessment of DBCP in drinking water. Adult male Sprague-Dawley rats were supplied ad libitum with water containing 0, 5, 50, 100, and 200 ppm DBCP for 64 days. A dose-related decrease in water consumption occurred during the study. The 200-ppm animals drank less than half as much water as controls, consumed less food, and subsequently exhibited significantly lower body weight gain. DBCP ingestion thus was not directly proportional to the level of chemical in the water, although daily and cumulative intake of DCP were concentration dependent. Average daily intake of DBCP for the 6Cday exposure period was as follows: 5 ppm = 0.4 m&kg/day; 50 ppm = 3.3 m&kg/day; 100 ppm = 5.4 mg/kg/day; 200 ppm = 9.7 mg&/day. Blood samples were taken after 2,4, and 6 weeks of exposure and at the terminal sacrifice and assayed for serum glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, sorbit dehydrogenase, and omithine-carbamyl transferase activities and BUN levels. No evidence of liver damage at any exposure level was indicated by either the clinical chemistry indices or histopathology. Histologic examination revealed an apparent increase in the number of nuclei per renal proximal tubule cross-section in the 200-ppm group, possibly indicative of an increased turnover of proximal tubular cells. A slight, but statistically significant, decrease in absolute testicular weight was manifest in the 200-ppm animals, although the decrease was not significant when testicular weight was calculated as g/ 100 g body wt. Epididymal sperm counts and serum luteinizing hormone, follicle stimulating hormone, and intratesticular testosterone levels were not altered by any dose of DBCP. A qualitative histopatholc&aI examina tion of the testicular seminiferous epithelium failed to reveal any abnormalities in the SpennatogenC process. 8 1989 sociay of Tmicdqy ' Supported in part by NIEHS Training Grant ES07090.
Endocrine disruptors and obesity
Nature reviews. Endocrinology, 2015
The increasing incidence of obesity is a serious global public health challenge. Although the obe... more The increasing incidence of obesity is a serious global public health challenge. Although the obesity epidemic is largely fueled by poor nutrition and lack of exercise, certain chemicals have been shown to potentially have a role in its aetiology. A substantial body of evidence suggests that a subclass of endocrine-disrupting chemicals (EDCs), which interfere with endocrine signalling, can disrupt hormonally regulated metabolic processes, especially if exposure occurs during early development. These chemicals, so-called 'obesogens' might predispose some individuals to gain weight despite their efforts to limit caloric intake and increase levels of physical activity. This Review discusses the role of EDCs in the obesity epidemic, the latest research on the obesogen concept, epidemiological and experimental findings on obesogens, and their modes of action. The research reviewed here provides knowledge that health scientists can use to inform their research and decision-making ...
Developmental Origins of Health and Disease: Integrating Environmental Influences
Endocrinology, Jan 4, 2015
There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) para... more There are now robust data supporting the Developmental Origins of Health and Disease (DOHaD) paradigm. This includes human and animal data focusing on nutrition or environmental chemicals during development. However, the term DOHaD has not been generally accepted as the official term to be used when one is concerned with understanding the pathophysiological basis for how environmental influences acting during early development influence the risk of later noncommunicable diseases. Similarly, there is no global research or public health program built around the DOHaD paradigm that encompasses all aspects of environment. To better inform the global health efforts aimed at addressing the growing epidemic of chronic noncommunicable diseases of environmental origin, we propose a two-pronged approach: first, to make it clear that the current concept of DOHaD comprehensively includes a range of environmental factors and their relevance to disease occurrence not just throughout the life span...
Current Environmental Health Reports, 2014
Obesity and diabetes have overtaken smoking as the number 1 preventable health determinate in the... more Obesity and diabetes have overtaken smoking as the number 1 preventable health determinate in the United States. In its basic form, obesity is due to disruptions of the endocrine systems that control food intake, satiety, and metabolic rate. Recent studies have identified a subclass of endocrine disrupting chemicals that interfere with hormonally regulated metabolic processes, especially during early development. These chemicals, called "obesogens," may predispose individuals to gain weight despite efforts to limit caloric intake and increase physical activity. Evidence suggests that chemical exposures early in life can predispose individuals to weight gain through programming changes, which may enhance dysfunctional eating behaviors later in life. This review examines the latest research on the obesogen hypothesis and its underpinnings in the Developmental Origins of Heath and Disease model. We provide examples of known and suspected obesogens, and evidence of their general mechanisms of action. The research reviewed here provides a solid foundation of knowledge from which health scientists may draw from and build upon to inform their research and decision-making.
Reproductive Toxicology, 2015
Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in... more Bisphenol A (BPA) is a chemical used in the production of numerous consumer products resulting in potential daily human exposure to this chemical. The FDA previously evaluated the toxicity of BPA and determined that it is safe at current exposure levels. This determination of BPA safety is not consistent with a body of literature from hypothesis driven studies and its safety continues to be debated in scientific and popular publications. Thus, the National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively a variety of hypothesis-based research investigations and guidelinecompliant safety testing with BPA. This collaboration is known as the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA). This paper provides a detailed description of the conduct of the study and a midterm update on progress of the CLARITY-BPA research program.
Endocrinology, Jan 4, 2015
The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expan... more The Developmental Origins of Health and Disease (DOHaD) paradigm is one of the most rapidly expanding areas of biomedical research. Environmental stressors that can impact on DOHaD encompass a variety of environmental and occupational hazards as well as deficiency and oversupply of nutrients and energy. They can disrupt early developmental processes and lead to increased susceptibility to disease/dysfunctions later in life. Presentations at the fourth Conference on Prenatal Programming and Toxicity in Boston, in October 2014, provided important insights and led to new recommendations for research and public health action. The conference highlighted vulnerable exposure windows that can occur as early as the preconception period and epigenetics as a major mechanism than can lead to disadvantageous "reprogramming" of the genome, thereby potentially resulting in transgenerational effects. Stem cells can also be targets of environmental stressors, thus paving another way for ef...