Work-related suicide: Evolving understandings of etiology & intervention.

Previously published analyses of suicide case investigations suggest that work or working conditions contribute to 10%-13% of suicide deaths. Yet, the way in which work may increase suicide risk is an underdeveloped area of epidemiologic research. In this Commentary, we propose a definition of work-related suicide from an occupational health and safety perspective, and review the case investigation-based and epidemiologic evidence on work-related causes of suicide. We identified six broad categories of potential work-related causes of suicide, which are: (1) workplace chemical, physical, and psychosocial exposures; (2) exposure to trauma on the job; (3) access to means of suicide through work; (4) exposure to high-stigma work environments; (5) exposure to normative environments promoting extreme orientation to work; and (6) adverse experiences arising from work-related injury or illness. We summarise current evidence in a schema of potential work-related causes that can also be applied in workplace risk assessment and suicide case investigations. There are numerous implications of these findings for policy and practice. Various principle- and evidence-based workplace intervention strategies for suicide prevention exist, some of which have been shown to improve suicide-prevention literacy, reduce stigma, enhance helping behaviours, and in some instances maybe even reduce suicide rates. Prevailing practice in workplace suicide prevention, however, overly emphasises individual- and illness-directed interventions, with little attention directed to addressing the working conditions that may increase suicide risk. We conclude that a stronger emphasis on improving working conditions will be required for workplace suicide prevention to reach its full preventive potential.

Associations between COVID-19-related changes in the psychosocial work environment and mental health.

BACKGROUND: Individuals' lives have been substantially affected by the COVID-19 pandemic. We aimed to describe changes in psychosocial work environment and mental health and to investigate associations between job insecurity and mental ill-health in relation to changes in other psychosocial work factors, loneliness and financial worries. METHODS: A sub-sample of individuals from the eighth Swedish Longitudinal Occupational Survey of Health answered a web-based survey in early 2021 about current and pandemic-related changes in health, health behaviours, work and private life. We investigated participants working before the pandemic (N=1231) in relation to standardised measures on depression, anxiety and loneliness, together with psychosocial work factors, in descriptive and logistic regression analyses. RESULTS: While 9% reached the clinical threshold for depression and 6% for anxiety, more than a third felt more worried, lonelier or in a low mood since the start of the pandemic. Two per cent had been dismissed from their jobs, but 16% experienced workplace downsizings. Conditioning on socio-demographic factors and prior mental-health problems, the 8% experiencing reduced job security during the pandemic had a higher risk of anxiety, but not of depression, compared to employees with unaltered or increased job security. Loneliness and other psychosocial work factors explained more of the association than objective measures of job insecurity and financial worries. CONCLUSIONS: Reduced job security during the COVID-19 pandemic seems to have increased the risk of anxiety among individuals with a strong labour market attachment, primarily via loneliness and other psychosocial work factors. This illustrates the potentially far-reaching effects of the pandemic on mental health in the working population.

Labor market exit around retirement age in Sweden and trajectories of psychotropic drugs in a context of downsizing.

BACKGROUND: A maintained psychological wellbeing is important in order to continue working longer and remain active into older age. However, little is known about impact of different organizational factors, such as downsizing, on the mental health of older workers exiting the labor market. The aim in this study was to investigate trajectories of purchases of psychotropic drugs in relation to labor market exit later in life in a context with and without downsizing. METHOD: People living in Sweden, born 1941-1951, exiting paid work via unemployment, sickness absence/disability pension, or old-age pension were followed from 2005 to 2013 regarding purchases of psychotropic drugs. Individuals employed at a workplace closing down or downsizing with ≥18% between two subsequent years were compared to employees exiting from workplaces without downsizing or workplace closure. Generalized estimating equations was applied to derive trajectories of annual prevalence of purchased antidepressants, sedatives and anxiolytics from 4 years before to 4 years after a labour market exit. RESULTS: During the period around the exit, old-age retirees experiencing a downsizing/workplace closure did not decrease their purchases of sedatives (OR 1.01 95% CI 0.95-1.07) while the unexposed decreased their purchases during this period (OR 0.95 95% CI 0.92-0.98). Similar differences concerning sedatives and antidepressants between exposed and unexposed were seen for those exiting via sickness absence or disability pension. Furthermore, a significant difference in purchases of anxiolytics was observed between those exposed to downsizing (OR 1.10 95% CI 0.97-1.24) and the unexposed (OR 0.98 95% CI 0.91-1.06) exiting via old-age retirement during the time before the exit. CONCLUSION: Downsizing or workplace closure, although weakly, was associated with higher prevalence of psychotropic drugs certain years around the labor market exit. The results support the idea that involuntary labor market exit in mature adulthood may negatively affect the development of mental health.

Increasing health inequalities between women in and out of work--the impact of recession or policy change? A repeated cross-sectional study in Stockholm county, 2006 and 2010.

INTRODUCTION: The social insurance system in Sweden underwent extensive change between 2006 and 2010, with the overall aim of making people enter the labour market. At the same time, economic recession hit Sweden. Previous studies suggest that the economic recession particularly affected women. In light of these changes, the aim of this study is to investigate whether health inequalities between employed women and groups outside the labour market changed between 2006 and 2010. A second aim is to examine the explanatory weight of socio-demographic factors vs social and economic conditions. METHODS: Data consists of the Stockholm Public Health Surveys (SPHS) for 2006 and 2010. Women aged 18-64 were studied. Through logistic regression, levels of mental distress and limiting longstanding illness (LLI), were compared between four labour market groups; employed and unemployed, sickness absentees and disability pension recipients, at the two time points. RESULTS: Mental distress increased among women in all four labour market groups between 2006 and 2010. Differences in mental distress between those employed and groups outside the labour market also increased. These were explained primarily by social and economic conditions. Levels of LLI were unchanged except among the unemployed. The difference in LLI between the unemployed and the employed was mostly explained by social and economic conditions. In the other groups socio-demographic factors were more salient. For both health outcomes, the weight of social and economic conditions had increased in 2010 compared to 2006. CONCLUSIONS: Results indicate that levels of mental distress increased in all groups, but more so among groups outside the labour market, possibly due to stricter eligibility criteria and lower benefit levels, which particularly affected their social and economic conditions.

Downsizing and purchases of psychotropic drugs: A longitudinal study of stayers, changers and unemployed.

BACKGROUND: The evidence is insufficient regarding the association between organizational downsizing and employee mental health. Our aim was to analyze trajectories of prescribed sedatives and anxiolytics with a sufficiently long follow-up time to capture anticipation, implementation and adaption to a downsizing event among stayers, changers and those who become unemployed compared to unexposed employees. METHOD: Residents in Sweden aged 20-54 years in 2007, with stable employment between 2004 and 2007, were followed between 2005 and 2013 (n = 2,305,795). Employment at a workplace with staff reductions ≥18% between two subsequent years in 2007-2011 (n = 915,461) indicated exposure to, and timing of, downsizing. The unexposed (n = 1,390,334) were randomized into four corresponding sub-cohorts. With generalized estimating equations, we calculated the odds ratios (OR) of purchasing prescribed anxiolytics or sedatives within nine 12-month periods, from four years before to four years after downsizing. In order to investigate whether the groups changed their probability of purchases over time, odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated contrasting the prevalence of purchases during the first and the last 12-month period within four time periods for each exposure group. RESULTS: The odds of purchasing psychotropic drugs increased more for changers (sedatives OR 1.08, 95% CI 1.05-1.11) and unemployed (anxiolytics OR 1.08, 95% CI 1.03-1.14), compared to unexposed before downsizing, while for stayers purchases increased more than for unexposed during and after downsizing. Among those without previous sickness absence, stayers increased their purchases of psychotropic drugs from the year before the event up to four years after the event. CONCLUSION: This study indicates that being exposed to downsizing is associated with increased use of sedatives and anxiolytics, before the event among those who leave, but especially thereafter for employees who stay in the organization.

Job loss and job instability during the COVID-19 pandemic and the risk of depression and anxiety among Swedish employees.

The COVID-19 pandemic led to permanent and temporary job losses but the mental health consequences of different types of employment transitions are not well-understood. In particular, knowledge is scarce concerning furloughs, which was a common job protection strategy in many high- and upper middle-income countries during this crisis. This study focuses on how different types of job instability and job loss during the pandemic influences depression and anxiety in the context of Sweden. A subset of participants from the Swedish Longitudinal Occupational Survey of Health were contacted in February 2021 and again in February 2022. A total of 1558 individuals participated in either or both waves and worked before the pandemic. We examined whether i) workplace downsizing, ii) furlough, or iii) unemployment/job loss were associated with depression and anxiety over this one-year period during the pandemic. Logistic regression models with cluster-robust standard errors were estimated, adjusting for sociodemographic factors and prior mental health problems. Effect modification by sex and prior mental health problems was also examined. In comparison to stable employment, being furloughed was unrelated to mental health, while experiencing workplace downsizing during the pandemic was associated with an increased risk of anxiety (adjusted Odds Ratio (OR) = 2.09, 95% Confidence interval (CI) = 1.08-4.05). Job loss/unemployment increased the risk of depression (OR = 1.91, 95% CI = 1.02-3.57) compared to being stably employed, but the risk estimate crossed unity when considering prior mental health status. No effect modification by sex or by prior mental health problems was found. This study found that while job loss and downsizing during the COVID-19 pandemic were associated with depression and anxiety, respectively, being furloughed was not. These findings thus suggest that job retention schemes in the form of short-time work allowances, as implemented in Sweden during the COVID-19 pandemic, may prevent mental health problems among employees during economic crises.

Distinguishing spirituality from other constructs: not a matter of well-being but of belief in supernatural spirits.

We developed a new Spirituality Scale and tested the argument that the defining attribute of spirituality is belief in supernatural spirits. Study 1 (N = 1931) showed that religiosity and beliefs pertinent to supernatural spirits predicted most of the variation in spirituality. Study 2 (N = 848) showed that the stronger belief in supernatural spirits, the more the person experienced subjective spirituality; that belief in supernatural spirits had higher predictive value of spirituality than religiosity, paranormal beliefs, or values; and that most of the relationship between religiosity and spirituality could be explained through belief in supernatural spirits. Study 3 (N = 972) showed that mental or physical health, social relationships, or satisfaction in marriage or work were not associated with spirituality. In turn, finding life purposeful and inner peace in dealing with spiritual experiences correlated with spirituality. The results highlight the importance of differentiating spirituality from other psychological constructs.

Perceived job insecurity and risk of suicide and suicide attempts: a study of men and women in the Swedish working population.

OBJECTIVE: Whether perceived job insecurity increases the risk of suicidal behaviors is unclear. Improved understanding in this area could inform efforts to reduce suicide risk among those experiencing elevated job insecurity during the COVID-19 pandemic as well as post-pandemic. We aimed to investigate if perceived job insecurity predicted increased risk of suicide mortality and suicide attempts. METHOD: Employees (N=65 571), representative of the Swedish working population who participated in the Swedish Work Environment Survey in 1991-2003, were followed up through 2016 in the National Inpatient and Death Registers. Suicide deaths and suicide attempts were defined according to International Classification of Diseases (ICD) 10 and ICD-8/9 codes of underlying cause of death and in-/outpatient care. Job insecurity and subsequent risk of suicide and suicide attempt were investigated with marginal structural Cox regression analyses and inverse probability of treatment weighting to control for confounding. RESULTS: Perceived job insecurity was associated with an elevated risk of suicide [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.03-2.20], but not with incident suicide attempts (HR 1.03, CI 0.86-1.24). Estimates remained similar after considering prevalent/previous poor mental health, other work factors, and when restricting the follow up time to ten years. CONCLUSION: The study suggests that job insecurity is associated with an increased risk of suicide mortality. Concerns about elevated job insecurity and suicide levels in the wake of the current pandemic could thus be considered in strategies to reduce the population health impact job insecurity both during and following the COVID-19 pandemic.

It's giving me the blues: A fixed-effects and g-formula approach to understanding job insecurity, sleep disturbances, and major depression.

Research suggests that work-related factors like job insecurity increases the risk of major depression (MD), although it is unclear whether the association is causal. Research further suggests that job insecurity increases sleep disturbances, which is also a risk factor for MD. Based on current knowledge, it is possible that job insecurity operates through sleep disturbances to affect MD, but this pathway has not been examined in the literature. The current study extends the literature by using two complementary, counterfactual approaches (i.e., random- and fixed-effects regression and a mediational g-formula) to examine whether job insecurity causes MD and whether sleep disturbances mediate the relationship. A methodological triangulation approach allowed us to adjust for unobserved and intermediate confounding, which has not been addressed in prior research. Findings suggest that the relationship between job insecurity and MD is primarily direct, that hypothetically intervening on job insecurity (in our g-formula) would reduce MD by approximately 10% at the population level, and this relationship operates via sleep disturbances to some degree. However, the indirect pathway had a high degree of uncertainty.

Associations between cognitive and affective job insecurity and incident purchase of psychotropic drugs: A prospective cohort study of Swedish employees.

BACKGROUND: Previous research suggests that job insecurity is associated with poor mental health, but research examining how different aspects of job insecurity relate to clinical measures of poor mental health are lacking. We aimed to investigate the association between cognitive and affective job insecurity and incident purchases of psychotropic drugs. METHODS: We included 14,586 employees participating in the Swedish Longitudinal Occupational Survey of Health (SLOSH), who answered questions on cognitive and/or affective job insecurity in 2010, 2012 or 2014. Respondents were followed in the Swedish Prescribed Drug Register (2.5 years on average). We investigated the association between job insecurity and incident psychotropic drugs with marginal structural Cox models. RESULTS: Affective job insecurity was associated with an increased risk of purchasing any psychotropic drugs (Hazard Ratio (HR) 1.40 (95% Confidence Interval (CI) 1.04-1.89)) while cognitive job insecurity was not (HR 1.15 (95% CI 0.92-1.43)). Cognitive and affective job insecurity were both associated with antidepressants, affective job insecurity with anxiolytics, but no association was found with sedatives. Women and younger workers seemed to have higher risk compared to men and older workers, but differences were not statistically significant. LIMITATIONS: Although job insecurity and psychotropic drugs were assessed through independent sources and several covariates were considered, unmeasured confounding cannot be ruled out. CONCLUSIONS: The findings support that affective job insecurity is a risk factor for psychotropic drug treatment, that it may be relevant to distinguish between different types of job insecurity, and to consider sex and age as moderating factors.

Downsizing and purchases of psychotropic drugs: A longitudinal study of stayers, changers and unemployed.

BACKGROUND: The evidence is insufficient regarding the association between organizational downsizing and employee mental health. Our aim was to analyze trajectories of prescribed sedatives and anxiolytics with a sufficiently long follow-up time to capture anticipation, implementation and adaption to a downsizing event among stayers, changers and those who become unemployed compared to unexposed employees. METHOD: Swedish residents aged 20-54 years in 2007, with stable employment between 2004 and 2007, were followed between 2005 and 2013 (n = 2,305,795). Employment at a workplace with staff reductions ≥18% between two subsequent years in 2007-2011 (n = 915,461) indicated exposure to, and timing of, downsizing. The unexposed (n = 1,390,334) were randomized into four corresponding sub-cohorts. With generalized estimating equations, we calculated the odds ratios (OR) of purchasing prescribed anxiolytics or sedatives within nine 12-month periods, from four years before to four years after downsizing. In order to investigate whether the groups changed their probability of purchases over time, odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated contrasting the prevalence of purchases during the first and the last 12-month period within four time periods for each exposure group. RESULTS: The odds of purchasing anxiolytics increased more for stayers (OR 1.03, 95% CI 1.01-1.06) and unemployed (OR 1.08, 95% CI 1.03-1.14) compared to unexposed before downsizing, and purchases continued to increase after downsizing for stayers. Among those without previous sickness absence, stayers increased their purchases of anxiolytics from the year before the event up to four years after the event. Trajectories for sedatives were similar but less pronounced. CONCLUSION: This study indicates that being exposed to downsizing is associated with increased use of sedatives and anxiolytics, especially before the event, if the employee stays in the organization or becomes unemployed.

Comparing Flow Cytometry QBeads PlexScreen Assays with Other Immunoassays for Determining Multiple Analytes.

Immunoassays, utilizing the affinity of antibodies to their antigens, are powerful techniques and have been widely used for quantifying analytes, such as cytokines, in biological samples in the clinic and in drug discovery. Various immunoassays have been developed to fit for different purposes. Recently, bead-based flow cytometry assays have emerged as interesting options for multiplex quantification of analytes. In this study, we compared high-throughput flow cytometry multiplex iQue QBeads PlexScreen assays with several other commonly used immunoassays, including MSD, Luminex, ELISA, HTRF, and AlphaLISA assays. Head-to-head comparisons of quantification data of the following cytokines were made: (1) IL-2, IL-4, IL-6, IL-13, IL-17A, IFNγ, KC/GRO, RANTES, and TNFα in mouse bronchoalveolar lavage fluid samples; (2) IL-10 and TNFα in supernatants from a THP-1 cell assay; (3) IL-6, IL-10, IL-12p70, and TNFα in supernatants from a human monocyte-derived dendritic cell assay; and (4) IL-2 in supernatants from a human CD4+ cell assay. The results demonstrated a good assay correlation between the iQue and the compared assays for the cytokine studied. Although overall good assay correlations were observed, our results showed that the iQue assay generated different absolute cytokine values for some cytokines in the same sample sets compared with other assays.

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors.

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1.

While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types - principal and intercalated cells - has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1(-/-) mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1(-/-) mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.

Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration.

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC50 > 9), and by careful manipulation of the pKa and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.

Adiponectin receptor 2 deficiency results in reduced atherosclerosis in the brachiocephalic artery in apolipoprotein E deficient mice.

Adiponectin has been shown to have beneficial cardiovascular effects and to signal through the adiponectin receptors, AdipoR1 and AdipoR2. The original aim of this study was to investigate the effect of combined AdipoR1 and AdipoR2 deficiency (AdipoR1(-/-)AdipoR2(-/-)) on atherosclerosis. However, we made the interesting observation that AdipoR1(-/-) AdipoR2(-/-) leads to embryonic lethality demonstrating the critical importance of the adiponectin signalling system during development. We then investigated the effect of AdipoR2-ablation on the progression of atherosclerosis in apolipoprotein E deficient (ApoE(-/-)) mice. AdipoR2(-/-)ApoE(-/-) mice fed an atherogenic diet had decreased plaque area in the brachiocephalic artery compared with AdipoR2(+/+) ApoE(-/-) littermate controls as visualized in vivo using an ultrasound biomicroscope and confirmed by histological analyses. The decreased plaque area in the brachiocephalic artery could not be explained by plasma cholesterol levels or inflammatory status. However, accumulation of neutral lipids was decreased in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice after incubation with oxidized LDL. This effect was associated with lower CD36 and higher ABCA1 mRNA levels in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice compared with AdipoR2(+/+)ApoE(-/-) controls after incubation with oxidized LDL. In summary, we show that adiponectin receptors are crucial during embryonic development and that AdipoR2-deficiency slows down the progression of atherosclerosis in the brachiocephalic artery of ApoE-deficient mice.

The forkhead transcription factor Foxi1 is a master regulator of vacuolar H-ATPase proton pump subunits in the inner ear, kidney and epididymis.

The vacuolar H(+)-ATPase dependent transport of protons across cytoplasmic membranes in FORE (forkhead related) cells of endolymphatic epithelium in the inner ear, intercalated cells of collecting ducts in the kidney and in narrow and clear cells of epididymis require expression of several subunits that assemble into a functional multimeric proton pump. We demonstrate that expression of four such subunits A1, B1, E2 and a4 all co-localize with the forkhead transcription factor Foxi1 in a subset of epithelial cells at these three locations. In cells, of such epithelia, that lack Foxi1 we fail to identify any expression of A1, B1, E2 and a4 demonstrating an important role for the transcription factor Foxi1 in regulating subunit availability. Promoter reporter experiments, electrophoretic mobility shift assays (EMSA) and site directed mutagenesis demonstrate that a Foxi1 expression vector can trans-activate an a4-promoter reporter construct in a dose dependent manner. Furthermore, we demonstrate using chromatin immunoprecipitation (ChIP) assays that Foxi1-dependent activation to a large extent depends on cis-elements at position -561/-547 in the a4 promoter. Thus, we provide evidence that Foxi1 is necessary for expression of at least four subunits in three different epithelia and most likely is a major determinant for proper assembly of a functional vacuolar H(+)-ATPase complex at these locations.

Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).

Although recessive mutations in the anion transporter gene SLC26A4 are known to be responsible for Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA), also known as "DFNB4," a large percentage of patients with this phenotype lack mutations in the SLC26A4 coding region in one or both alleles. We have identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOXI1, a transcriptional activator of SLC26A4. In nine patients with PS or nonsyndromic EVA, a novel c.-103T-->C mutation in this regulatory element interferes with FOXI1 binding and completely abolishes FOXI1-mediated transcriptional activation. We have also identified six patients with mutations in FOXI1 that compromise its ability to activate SLC26A4 transcription. In one family, the EVA phenotype segregates in a double-heterozygous mode in the affected individual who carries single mutations in both SLC26A4 and FOXI1. This finding is consistent with our observation that EVA occurs in the Slc26a4(+/-); Foxi1(+/-) double-heterozygous mouse mutant. These results support a novel dosage-dependent model for the molecular pathogenesis of PS and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery.

Epididymal expression of the forkhead transcription factor Foxi1 is required for male fertility.

An essential aspect of male reproductive capacity is the immediate availability of fertilization-ready spermatozoa. To ensure this, most mammals rely on post-testicular sperm maturation. In epididymis, germ cells are matured and stored in a quiescent state that readily can be altered to produce active spermatozoa. This depends on active proton secretion into the epididymal lumen. We have identified Foxi1 as an important regulator of gene expression in narrow and clear cells-the major proton secretory cells of epididymal epithelia. Foxi1 appears to be required for the expression of the B1-subunit of the vacuolar H+ -ATPase proton pump and for carbonic anhydrase II as well as the chloride/bicarbonate transporter pendrin. Using transfection experiments, we have identified a Foxi1 binding cis-element in the ATP6V1B1 (encoding the B1-subunit) promoter that is critical for reporter gene activation. When this site is mutated to eliminate Foxi1 binding, activation is also abolished. As a consequence of defect Foxi1-dependent epididymal sperm maturation, we demonstrate that spermatozoa from Foxi1 null males fail to reach the female genital tract in sufficient number to allow fertilization.