Proposed Key Characteristics of Male Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Evidence in Human Health Hazard Assessments.

BACKGROUND: Assessing chemicals for their potential to cause male reproductive toxicity involves the evaluation of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in hazard identification and evidence integration, the process of identifying, screening and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods and the variety of known and proposed pathways for chemical-induced toxicity. Ten key characteristics of carcinogens provide a valuable tool for organizing and assessing chemical-specific data by potential mechanisms for cancer-causing agents. However, such an approach has not yet been developed for noncancer adverse outcomes. OBJECTIVES: The objective in this study was to identify a set of key characteristics that are frequently exhibited by exogenous agents that cause male reproductive toxicity and that could be applied for identifying, organizing, and summarizing mechanistic evidence related to this outcome. DISCUSSION: The identification of eight key characteristics of male reproductive toxicants was based on a survey of known male reproductive toxicants and established mechanisms and pathways of toxicity. The eight key characteristics can provide a basis for the systematic, transparent, and objective organization of mechanistic evidence relevant to chemical-induced effects on the male reproductive system. https://doi.org/10.1289/EHP5045.

Les†lanternes†rouges: the race for information about cycling-related female sexual dysfunction.

INTRODUCTION: Cycling is growing in popularity among women. As in men, it is associated with genital neuropathies and decreased sensation in female riders. However, there is a gap in research and information addressing the relationship between cycling and female sexual dysfunction (FSD) in women. AIMS: To review the literature investigating pelvic floor injuries and sexual dysfunction in female cyclists. METHODS: Searches in several electronic databases were conducted, and relevant articles that met the inclusion criteria were identified for critical review. MAIN OUTCOME MEASURES: The main outcome measure to be determined was the strength of the current body of evidence in published literature of a correlation between cycling-related pelvic floor injuries and FSD. RESULTS: Data on FSD from cycling-related injuries in women are limited. Research indicates that bicycle setup and riding equipment may be contributing factors. Women's ergonomics and physiology interact differently with the bicycle than men's. Current evidence offers insufficient foundation to recommend various effect-mitigating equipment and products. CONCLUSIONS: While gender-specific cycling products offer a promising direction for protecting women riders, studies addressing FSD and pelvic floor injuries in women cyclists are inadequate to indicate clear etiology or provide treatment recommendations. Current evidence is also insufficient to recommend effect-mitigating equipment and products.

Assessing the reproductive health of men with occupational exposures.

The earliest report linking environmental (occupational) exposure to adverse human male reproductive effects dates back to1775 when an English physician, Percival Pott, reported a high incidence of scrotal cancer in chimney sweeps. This observation led to safety regulations in the form of bathing requirements for these workers. The fact that male-mediated reproductive harm in humans may be a result of toxicant exposures did not become firmly established until relatively recently, when Lancranjan studied lead-exposed workers in Romania in 1975, and later in 1977, when Whorton examined the effects of dibromochloropropane (DBCP) on male workers in California. Since these discoveries, several additional human reproductive toxicants have been identified through the convergence of laboratory and observational findings. Many research gaps remain, as the pool of potential human exposures with undetermined effects on male reproduction is vast. This review provides an overview of methods used to study the effects of exposures on male reproduction and their reproductive health, with a primary emphasis on the implementation and interpretation of human studies. Emphasis will be on occupational exposures, although much of the information is also useful in assessing environmental studies, occupational exposures are usually much higher and better defined.

Evaluation of the effectiveness of semen storage and sperm purification methods for spermatozoa transcript profiling.

Different semen storage and sperm purification methods may affect the integrity of isolated spermatozoal RNA. RNA-Seq was applied to determine whether semen storage methods (pelleted vs. liquefied) and somatic cell lysis buffer (SCLB) vs. PureSperm (PS) purification methods affect the quantity and quality of sperm RNA. The results indicate that the method of semen storage does not markedly impact RNA profiling whereas the choice of purification can yield significant differences. RNA-Seq showed that the majority of mitochondrial and mid-piece associated transcripts were lost after SCLB purification, which indicated that the mid-piece of spermatozoa may have been compromised. In addition, the number of stable transcript pairs from SCLB-samples was less than that from the PS samples. This study supports the view that PS purification better maintains the integrity of spermatozoal RNAs.

Occupational exposure to acrylamide in closed system production plants: air levels and biomonitoring.

The aim of this study was to evaluate biomarkers of acrylamide exposure, including hemoglobin adducts and urinary metabolites in acrylamide production workers. Biomarkers are integrated measures of the internal dose, and it is total acrylamide dose from all routes and sources that may present health risks. Workers from three companies were studied. Workers potentially exposed to acrylamide monomer wore personal breathing-zone air samplers. Air samples and surface-wipe samples were collected and analyzed for acrylamide. General-area air samples were collected in chemical processing units and control rooms. Hemoglobin adducts were isolated from ethylenediamine teraacetic acid (EDTA)-whole blood, and adducts of acrylamide and glycidamide, at the N-terminal valines of hemoglobin, were cleaved from the protein chain by use of a modified Edman reaction. Full work-shift, personal breathing zone, and general-area air samples were collected and analyzed for particulate and acrylamide monomer vapor. The highest general-area concentration of acrylamide vapor was 350 µg/cm(3) in monomer production. Personal breathing zone and general-area concentrations of acrylamide vapor were found to be highest in monomer production operations, and lower levels were in the polymer production operations. Adduct levels varied widely among workers, with the highest in workers in the monomer and polymer production areas. The acrylamide adduct range was 15-1884 pmol/g; glycidamide adducts ranged from 17.8 to 1376 p/mol/g. The highest acrylamide and glycidamide adduct levels were found among monomer production process operators. The primary urinary metabolite N-acetyl-S-(2-carbamoylethyl) cysteine (NACEC) ranged from the limit of detection to 15.4 µg/ml. Correlation of workplace exposure and sentinel health effects is needed to determine and control safe levels of exposure for regulatory standards.

Pubertal delay in male nonhuman primates (Macaca mulatta) treated with methylphenidate.

Juvenile male rhesus monkeys treated with methylphenidate hydrochloride (MPH) to evaluate genetic and behavioral toxicity were observed after 14 mo of treatment to have delayed pubertal progression with impaired testicular descent and reduced testicular volume. Further evaluation of animals dosed orally twice a day with (i) 0.5 mL/kg of vehicle (n = 10), (ii) 0.15 mg/kg of MPH increased to 2.5 mg/kg (low dose, n = 10), or (iii) 1.5 mg/kg of MPH increased to 12.5 mg/kg (high dose, n = 10) for a total of 40 mo revealed that testicular volume was significantly reduced (P < 0.05) at months 15 to 19 and month 27. Testicular descent was significantly delayed (P < 0.05) in the high-dose group. Significantly lower serum testosterone levels were detected in both the low- (P = 0.0017) and high-dose (P = 0.0011) animals through month 33 of treatment. Although serum inhibin B levels were increased overall in low-dose animals (P = 0.0328), differences between groups disappeared by the end of the study. Our findings indicate that MPH administration, beginning before puberty, and which produced clinically relevant blood levels of the drug, impaired pubertal testicular development until ∼5 y of age. It was not possible to resolve whether MPH delayed the initiation of the onset of puberty or reduced the early tempo of the developmental process. Regardless, deficits in testicular volume and hormone secretion disappeared over the 40-mo observation period, suggesting that the impact of MPH on puberty is not permanent.

Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development--the LIFE Study.

The relationship between the environment and human fecundity and fertility remains virtually unstudied from a couple-based perspective in which longitudinal exposure data and biospecimens are captured across sensitive windows. In response, we completed the LIFE Study with methodology that intended to empirically evaluate a priori purported methodological challenges: implementation of population-based sampling frameworks suitable for recruiting couples planning pregnancy; obtaining environmental data across sensitive windows of reproduction and development; home-based biospecimen collection; and development of a data management system for hierarchical exposome data. We used two sampling frameworks (i.e., fish/wildlife licence registry and a direct marketing database) for 16 targeted counties with presumed environmental exposures to persistent organochlorine chemicals to recruit 501 couples planning pregnancies for prospective longitudinal follow-up while trying to conceive and throughout pregnancy. Enrolment rates varied from <1% of the targeted population (n = 424,423) to 42% of eligible couples who were successfully screened; 84% of the targeted population could not be reached, while 36% refused screening. Among enrolled couples, ∼ 85% completed daily journals while trying; 82% of pregnant women completed daily early pregnancy journals, and 80% completed monthly pregnancy journals. All couples provided baseline blood/urine samples; 94% of men provided one or more semen samples and 98% of women provided one or more saliva samples. Women successfully used urinary fertility monitors for identifying ovulation and home pregnancy test kits. Couples can be recruited for preconception cohorts and will comply with intensive data collection across sensitive windows. However, appropriately sized sampling frameworks are critical, given the small percentage of couples contacted found eligible and reportedly planning pregnancy at any point in time.

Cutting off the nose to save the penis.

INTRODUCTION: The average bicycle police officer spends 24 hours a week on his bicycle and previous studies have shown riding a bicycle with a traditional (nosed) saddle has been associated with urogenital paresthesia and sexual dysfunction. AIM: The objective of this study was to assess the effectiveness of the no-nose bicycle saddle as an ergonomic intervention and their acceptance among male bicycle police officers. METHODS: Bicycle police officers from five U.S. metropolitan areas were recruited for this study. Officers completed: (i) the International Index of Erectile Function Questionnaire (IIEF); (ii) computerized pressure measurements at the points of contact on the bicycle; the handlebars, the pedals, and the saddle; (iii) one night of nocturnal Rigiscan assessment; (iv) penile vibrotactile sensitivity threshold assessed by computerized biothesiometery. Officers selected a no-nose saddle for their bicycles and were asked to use the intervention saddle exclusively for 6 months, at which point they were retested. MAIN OUTCOME MEASURES: Perineal pressure, urogenital numbness, penile vibrotactile sensitivity threshold, erectile function as measure by International Index of Erectile Function Questionnaire (IIEF) and Rigiscan. RESULTS: After 6 months, 90 men were reassessed. Only three men had returned to a traditional saddle. The results are presented for those who used the no-nose saddle continuously for 6 months. There was a 66% reduction in saddle contact pressure in the perineal region (P < 0.001). There was a significant improvement in penis tactile sensation (P = 0.015). There was a significant improvement in erectile function assessed by IIEF (P = 0.015). There were no changes noted in the Rigiscan measures. The number of men indicating they had not experienced urogential paresthesia while cycling for the preceding 6 months, rose from 27% to 82% using no-nose saddles. CONCLUSIONS: (i) With few exceptions, bicycle police officers were able to effectively use no-nose saddles in their police work. (ii) Use of no-nose saddles reduced most perineal pressure. (iii) Penile health improved after 6 month using no-nose saddles as measured by biothesiometry and IIEF. There was no improvement in Rigiscan(R) measure after 6 months of using no nose saddles, suggesting that a longer recovery time may be needed..

Effect of bicycle saddle designs on the pressure to the perineum of the bicyclist.

PURPOSE: Increasing awareness of an association between bicycling and male sexual dysfunction has led to the appearance of a variety of bicycle saddles that share the design objective of reducing pressure in the groin of the cyclist by removal of the narrow protruding nose of the saddle. This study compared three of these saddle designs to a traditional sport/road racing saddle with a narrow protruding nose in terms of pressure in the region of the perineum (groin) of the cyclist. METHODS: Saddle, pedal, and handlebar contact pressure were measured from 33 bicycle police patrol officers pedaling a stationary bicycle at a controlled cadence and workload. Pressure was characterized over the saddle as a whole and over a region of the saddle assumed to represent pressure on the cyclist's perineum located anteriorly to the ischial tuberosities. RESULTS: The traditional sport/racing saddle was associated with more than two times the pressure in the perineal region than the saddles without a protruding nose (P < 0.01). There were no significant differences in perineal pressure among the nontraditional saddles. Measures of load on the pedals and handlebars indicated no differences between the traditional saddle and those without protruding noses. This finding is contradictory to those studies suggesting a shift toward greater weight distribution on the handlebars and pedals when using a saddle without a nose. CONCLUSIONS: The recommendation of a saddle without a narrow protruding nose appears to be justified to reduce pressure to the perineum of the bicyclist.

Prospective pregnancy study designs for assessing reproductive and developmental toxicants.

The determinants of successful human reproduction and development may act as early as periconceptionally, underscoring the need to capture exposures during these critical windows when assessing potential toxicants. To identify such toxicants, couples must be studied longitudinally prior to conception without regard to a couple's ability to ascertain a clinically recognized pregnancy. We examined the utility and feasibility of prospective pregnancy study designs by conducting a systematic review of the literature to summarize relevant information regarding the planning, implementation, and success of previously published prospective pregnancy studies. Information concerning design elements and participation was abstracted from 15 eligible studies (from a total of 20 identified studies) using a standardized form. The primary author of each study was contacted to review our summary of their work and obtain missing information. Our findings confirm the ability to recruit women/couples from diverse populations using a variety of recruitment strategies. Among the studies we reviewed, 4-97% of eligible individuals were successfully contacted, with enrollment rates ranging from 42 to 100%. Length of follow-up varied from 3 to 12 months. A high percentage of women provided urine (57-98%) and blood (86-91%) specimens and most male partners (94-100%) provided semen samples. These data support the feasibility of this design.

An occupational reproductive research agenda for the third millennium.

There is a significant public health concern about the potential effects of occupational exposure to toxic substances on reproductive outcomes. Several toxicants with reported reproductive and developmental effects are still in regular commercial or therapeutic use and thus present potential exposure to workers. Examples of these include heavy metals, organic solvents, pesticides and herbicides, and sterilants, anesthetic gases, and anticancer drugs used in health care. Many other substances are suspected of producing reproductive or developmental toxicity but lack sufficient data. Progress has been limited in identifying hazards and quantifying their potencies and in separating the contribution of these hazards from other etiologic factors. Identifying the causative agents, mechanisms by which they act, and any potential target populations, present the opportunity to intervene and protect the reproductive health of workers. The pace of laboratory studies to identify hazards and to underpin the biologic plausibility of effects in humans has not matched the pace at which new chemicals are introduced into commerce. Though many research challenges exist today, recent technologic and methodologic advances have been made that allow researchers to overcome some of these obstacles. The objective of this article is to recommend future directions in occupational reproductive health research. By bridging interdisciplinary gaps, the scientific community can work together to improve health and reduce adverse outcomes.

Nocturnal penile tumescence and rigidity testing in bicycling patrol officers.

A health assessment study was conducted in response to complaints of groin numbness in a bicycling police unit. Seventeen male cyclists were compared with 5 nonbiking men. The cyclists rode an average of 5.4 hours per day, and 91% indicated they experienced groin numbness on occasion. Each man wore the RigiScan Plus Rigidity Assessment System for one normal sleep session. Pressure measurements were also taken between the cyclist and the bicycle saddle. The percentage of sleep sessions that recorded an erectile event was significantly lower in the cyclists than it was in noncyclists (cyclists 27.1%; noncyclists 42.8%; P =.008). This duration percentage is negatively correlated with average hours a day that cyclists rode their bikes (r = -.41; P =.05), the number of days a week they rode (r = -.55; P =.009), and the average pressure exerted on the nose of the bike saddle (r = -.39; P =.08). The other measures of erectile quality (tumescence activity units [TAUs] and rigidity activity units [RAUs] of both the base and tip of the penis) were lower in the cyclists, but did not reach statistical significance. The number of hours cyclists rode during the day of RigiScan Plus assessment was negatively correlated with penis tip RAU (r = -.41; P =.04), and tip TAU (r = -.45; P =.04). These data suggest that prolonged bicycle riding may have negative effects on nocturnal erectile function and indicate a need for innovative bicycle saddle designs.